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Wei X, Yang M, Zou H, Shen S, Li Y, Chen L, Liu Y, Li D, Ding J. Poly(amino acid) nanoformulation of cyclin-dependent kinase 4 and 6 inhibitor for molecularly targeted immunotherapy in triple-negative breast cancer. J Control Release 2025; 380:760-772. [PMID: 39947403 DOI: 10.1016/j.jconrel.2025.02.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 02/07/2025] [Accepted: 02/08/2025] [Indexed: 02/21/2025]
Abstract
Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) selectively arrest malignant cells in the G1 phase of cell cycle by inhibiting CDK4/6-mediated phosphorylation of retinoblastoma protein. However, CDK4/6i therapy is often ineffective against triple-negative breast cancer (TNBC) due to the high lysosomal content in TNBC cells, which sequesters the drugs and prevents them from reaching their nuclear target. To address this challenge, three pH- and glutathione-responsive poly(amino acid) nanogels composed of methoxy poly(ethylene glycol) of various lengths and poly(L-glutamic acid-co-L-cystine) (mPEG-P(Glu10-co-Cys25)) were developed to efficiently deliver the CDK4/6i abemaciclib (ABE) to TNBC cells. These nanogels bypassed lysosomal sequestration, thereby enhancing the efficacy of molecularly targeted immunotherapy. Among the nanogels, the formulation with mPEG2000 (NG2000) exhibited the highest efficiency in delivering ABE, resulting in increased cell apoptosis, activation of an anti-cancer immune response, reduction of immunosuppression, and improved therapeutic outcomes against TNBC. Furthermore, NG2000/ABE enhanced immune checkpoint therapy for TNBC, achieving a tumor inhibition rate of 89.66%. These findings demonstrate the potential of poly(amino acid) nanoformulations for delivering CDK4/6 inhibitors as molecularly targeted immunotherapy for TNBC in clinical applications.
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Affiliation(s)
- Xue Wei
- Department of Breast Surgery, General Surgery Center, The First Hospital of Jilin University, 1 Xinmin Street, Changchun 130061, PR China; Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, PR China
| | - Ming Yang
- Department of Breast Surgery, General Surgery Center, The First Hospital of Jilin University, 1 Xinmin Street, Changchun 130061, PR China.
| | - Haoyang Zou
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, PR China
| | - Songjie Shen
- Department of Breast Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, 1 Shuaifuyuan, Beijing 100730, PR China
| | - Yuechong Li
- Department of Breast Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, 1 Shuaifuyuan, Beijing 100730, PR China
| | - Li Chen
- Department of Chemistry, Northeast Normal University, 5268 Renmin Street, Changchun 130024, PR China
| | - Yahui Liu
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, 1 Xinmin Street, Changchun 130061, PR China.
| | - Di Li
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, 1 Xinmin Street, Changchun 130061, PR China
| | - Jianxun Ding
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, PR China
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2
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Scheiblecker L, Klampfl T, Doma E, Nebenfuehr S, Torres-Quesada O, Strich S, Heller G, Werdenich D, Tschulenk W, Zojer M, Bellutti F, Schirripa A, Zöchbauer-Müller S, Valent P, Walter I, Stefan E, Sexl V, Kollmann K. CDK6 kinase inhibition unmasks metabolic dependencies in BCR::ABL1+ leukemia. Cell Death Dis 2025; 16:107. [PMID: 39966356 PMCID: PMC11836434 DOI: 10.1038/s41419-025-07434-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 01/15/2025] [Accepted: 02/06/2025] [Indexed: 02/20/2025]
Abstract
Metabolic reprogramming and cell cycle deregulation are hallmarks of cancer cells. The cell cycle kinase CDK6 has recently been implicated in a wide range of hematopoietic malignancies. We here investigate the role of CDK6 in the regulation of cellular metabolism in BCR::ABL1+ leukemic cells. Our study, using gene expression data and ChIP-Seq analysis, highlights the contribution of CDK6 kinase activity in the regulation of oxidative phosphorylation. Our findings imply a competition for promoter interaction of CDK6 with the master regulator of mitochondrial respiration, NRF-1. In line, cells lacking kinase active CDK6 display altered mitochondria morphology with a defective electron transport chain. The enhanced cytoplasm/mitochondria ATP ratio paralleled by high pyruvate and lactate levels indicate a metabolic switch to glycolysis. Accordingly, combinatorial treatment of leukemic cells including imatinib resistant cells with the CDK4/6 inhibitor palbociclib and the glycolysis inhibitor 2-deoxyglucose (2-DG) enhanced apoptosis, while blocking cell proliferation in leukemic cells. These data may open a new therapeutic avenue for hematologic malignancies with high CDK6 expression by exploiting metabolic vulnerabilities unmasked by blocking CDK6 kinase activity that might even be able to overcome imatinib resistance.
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Affiliation(s)
- Lisa Scheiblecker
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Thorsten Klampfl
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Eszter Doma
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Sofie Nebenfuehr
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Omar Torres-Quesada
- Institute of Medical Biochemistry, Medical University of Innsbruck, Innsbruck, Austria
- Tyrolean Cancer Research Institute (TKFI), Innsbruck, Austria
| | - Sophie Strich
- Institute of Medical Biochemistry, Medical University of Innsbruck, Innsbruck, Austria
- Tyrolean Cancer Research Institute (TKFI), Innsbruck, Austria
- Institute of Molecular Biology and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria
| | - Gerwin Heller
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Daniela Werdenich
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Waltraud Tschulenk
- Institute of Morphology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Markus Zojer
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Florian Bellutti
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Alessia Schirripa
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Sabine Zöchbauer-Müller
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Peter Valent
- Division of Hematology and Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
| | - Ingrid Walter
- Institute of Morphology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Eduard Stefan
- Tyrolean Cancer Research Institute (TKFI), Innsbruck, Austria
- Institute of Molecular Biology and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria
| | - Veronika Sexl
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria
- University of Innsbruck, Innsbruck, Austria
| | - Karoline Kollmann
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria.
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3
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Longhurst AD, Wang K, Suresh HG, Ketavarapu M, Ward HN, Jones IR, Narayan V, Hundley FV, Hassan AZ, Boone C, Myers CL, Shen Y, Ramani V, Andrews BJ, Toczyski DP. The PRC2.1 subcomplex opposes G1 progression through regulation of CCND1 and CCND2. eLife 2025; 13:RP97577. [PMID: 39903505 PMCID: PMC11793871 DOI: 10.7554/elife.97577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2025] Open
Abstract
Progression through the G1 phase of the cell cycle is the most highly regulated step in cellular division. We employed a chemogenetic approach to discover novel cellular networks that regulate cell cycle progression. This approach uncovered functional clusters of genes that altered sensitivity of cells to inhibitors of the G1/S transition. Mutation of components of the Polycomb Repressor Complex 2 rescued proliferation inhibition caused by the CDK4/6 inhibitor palbociclib, but not to inhibitors of S phase or mitosis. In addition to its core catalytic subunits, mutation of the PRC2.1 accessory protein MTF2, but not the PRC2.2 protein JARID2, rendered cells resistant to palbociclib treatment. We found that PRC2.1 (MTF2), but not PRC2.2 (JARID2), was critical for promoting H3K27me3 deposition at CpG islands genome-wide and in promoters. This included the CpG islands in the promoter of the CDK4/6 cyclins CCND1 and CCND2, and loss of MTF2 lead to upregulation of both CCND1 and CCND2. Our results demonstrate a role for PRC2.1, but not PRC2.2, in antagonizing G1 progression in a diversity of cell linages, including chronic myeloid leukemia (CML), breast cancer, and immortalized cell lines.
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Affiliation(s)
- Adam D Longhurst
- University of California, San FranciscoSan FranciscoUnited States
- Tetrad Graduate Program, University of California, San FranciscoSan FranciscoUnited States
| | - Kyle Wang
- Department of Molecular Genetics, University of TorontoTorontoCanada
- The Donnelly Centre for Cellular and Biomolecular Research, University of TorontoTorontoCanada
| | | | - Mythili Ketavarapu
- Gladstone Institute for Data Science and Biotechnology, J. David Gladstone InstitutesSan FranciscoUnited States
- Department of Biochemistry and Biophysics, University of California, San FranciscoSan FranciscoUnited States
| | - Henry N Ward
- Bioinformatics and Computational Biology Graduate Program, University of Minnesota – Twin Cities MinneapolisMinneapolisUnited States
| | - Ian R Jones
- Institute for Human Genetics, University of California, San FranciscoSan FranciscoUnited States
- Pharmaceutical Sciences and Pharmacogenomics Graduate Program, University of California, San FranciscoSan FranciscoUnited States
| | - Vivek Narayan
- Institute for Human Genetics, University of California, San FranciscoSan FranciscoUnited States
| | - Frances V Hundley
- University of California, San FranciscoSan FranciscoUnited States
- Tetrad Graduate Program, University of California, San FranciscoSan FranciscoUnited States
- Department of Cell Biology, Blavatnik Institute of Harvard Medical SchoolBostonUnited States
| | - Arshia Zernab Hassan
- Department of Computer Science and Engineering, University of Minnesota – Twin Cities MinneapolisMinneapolisUnited States
| | - Charles Boone
- Department of Molecular Genetics, University of TorontoTorontoCanada
- The Donnelly Centre for Cellular and Biomolecular Research, University of TorontoTorontoCanada
| | - Chad L Myers
- Bioinformatics and Computational Biology Graduate Program, University of Minnesota – Twin Cities MinneapolisMinneapolisUnited States
- Department of Cell Biology, Blavatnik Institute of Harvard Medical SchoolBostonUnited States
| | - Yin Shen
- Institute for Human Genetics, University of California, San FranciscoSan FranciscoUnited States
- Department of Neurology, University of California, San FranciscoSan FranciscoUnited States
- Weill Institute for Neurosciences, University of California, San FranciscoSan FranciscoUnited States
| | - Vijay Ramani
- Gladstone Institute for Data Science and Biotechnology, J. David Gladstone InstitutesSan FranciscoUnited States
- Department of Biochemistry and Biophysics, University of California, San FranciscoSan FranciscoUnited States
| | - Brenda J Andrews
- The Donnelly Centre for Cellular and Biomolecular Research, University of TorontoTorontoCanada
| | - David P Toczyski
- University of California, San FranciscoSan FranciscoUnited States
- Department of Biochemistry and Biophysics, University of California, San FranciscoSan FranciscoUnited States
- Weill Institute for Neurosciences, University of California, San FranciscoSan FranciscoUnited States
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4
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Storaci AM, Bertolini I, Martelli C, De Turris G, Mansour N, Crosti M, De Filippo MR, Ottobrini L, Valenti L, Polledri E, Fustinoni S, Caroli M, Fanizzi C, Bosari S, Ferrero S, Zadra G, Vaira V. V-ATPase in glioma stem cells: a novel metabolic vulnerability. J Exp Clin Cancer Res 2025; 44:17. [PMID: 39825382 PMCID: PMC11740391 DOI: 10.1186/s13046-025-03280-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Accepted: 01/08/2025] [Indexed: 01/20/2025] Open
Abstract
BACKGROUND Glioblastoma (GBM) is a lethal brain tumor characterized by the glioma stem cell (GSC) niche. The V-ATPase proton pump has been described as a crucial factor in sustaining GSC viability and tumorigenicity. Here we studied how patients-derived GSCs rely on V-ATPase activity to sustain mitochondrial bioenergetics and cell growth. METHODS V-ATPase activity in GSC cultures was modulated using Bafilomycin A1 (BafA1) and cell viability and metabolic traits were analyzed using live assays. The GBM patients-derived orthotopic xenografts were used as in vivo models of disease. Cell extracts, proximity-ligation assay and advanced microscopy was used to analyze subcellular presence of proteins. A metabolomic screening was performed using Biocrates p180 kit, whereas transcriptomic analysis was performed using Nanostring panels. RESULTS Perturbation of V-ATPase activity reduces GSC growth in vitro and in vivo. In GSC there is a pool of V-ATPase that localize in mitochondria. At the functional level, V-ATPase inhibition in GSC induces ROS production, mitochondrial damage, while hindering mitochondrial oxidative phosphorylation and reducing protein synthesis. This metabolic rewiring is accompanied by a higher glycolytic rate and intracellular lactate accumulation, which is not exploited by GSCs for biosynthetic or survival purposes. CONCLUSIONS V-ATPase activity in GSC is critical for mitochondrial metabolism and cell growth. Targeting V-ATPase activity may be a novel potential vulnerability for glioblastoma treatment.
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Affiliation(s)
- Alessandra Maria Storaci
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
- Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Irene Bertolini
- Molecular and Cellular Oncogenesis Program, Wistar Institute, Philadelphia, PA, USA
| | - Cristina Martelli
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Giorgia De Turris
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Nadia Mansour
- Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Mariacristina Crosti
- INGM, Istituto Nazionale Di Genetica Molecolare "Romeo Ed Enrica Invernizzi", 20122, Milan, Italy
| | | | - Luisa Ottobrini
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Luca Valenti
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
- Department of Transfusion Medicine, Precision Medicine Lab, Biological Resource Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Elisa Polledri
- EPIGET-Epidemiology, Epigenetics, and Toxicology Lab, Department of Clinical Sciences and Community Health, University of Milan, 20122, Milan, Italy
| | - Silvia Fustinoni
- EPIGET-Epidemiology, Epigenetics, and Toxicology Lab, Department of Clinical Sciences and Community Health, University of Milan, 20122, Milan, Italy
- Environmental and Industrial Toxicology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122, Milan, Italy
| | - Manuela Caroli
- Division of Neurosurgery, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Claudia Fanizzi
- Division of Neurosurgery, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Silvano Bosari
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Stefano Ferrero
- Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122, Milan, Italy
| | - Giorgia Zadra
- Institute of Molecular Genetics, National Research Council (CNR-IGM), 27100, Pavia, Italy
| | - Valentina Vaira
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
- Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
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5
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Ziegler DV, Parashar K, Leal-Esteban L, López-Alcalá J, Castro W, Zanou N, Martinez-Carreres L, Huber K, Berney XP, Malagón MM, Roger C, Berger MA, Gouriou Y, Paone G, Gallart-Ayala H, Sflomos G, Ronchi C, Ivanisevic J, Brisken C, Rieusset J, Irving M, Fajas L. CDK4 inactivation inhibits apoptosis via mitochondria-ER contact remodeling in triple-negative breast cancer. Nat Commun 2025; 16:541. [PMID: 39788939 PMCID: PMC11718081 DOI: 10.1038/s41467-024-55605-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Accepted: 12/18/2024] [Indexed: 01/12/2025] Open
Abstract
The energetic demands of proliferating cells during tumorigenesis require close coordination between the cell cycle and metabolism. While CDK4 is known for its role in cell proliferation, its metabolic function in cancer, particularly in triple-negative breast cancer (TNBC), remains unclear. Our study, using genetic and pharmacological approaches, reveals that CDK4 inactivation only modestly impacts TNBC cell proliferation and tumor formation. Notably, CDK4 depletion or long-term CDK4/6 inhibition confers resistance to apoptosis in TNBC cells. Mechanistically, CDK4 enhances mitochondria-endoplasmic reticulum contact (MERCs) formation, promoting mitochondrial fission and ER-mitochondrial calcium signaling, which are crucial for TNBC metabolic flexibility. Phosphoproteomic analysis identified CDK4's role in regulating PKA activity at MERCs. In this work, we highlight CDK4's role in mitochondrial apoptosis inhibition and suggest that targeting MERCs-associated metabolic shifts could enhance TNBC therapy.
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Affiliation(s)
- Dorian V Ziegler
- Center for Integrative Genomics, University of Lausanne, Faculty of Biology and Medicine, Lausanne, Switzerland
| | - Kanishka Parashar
- Center for Integrative Genomics, University of Lausanne, Faculty of Biology and Medicine, Lausanne, Switzerland
| | - Lucia Leal-Esteban
- Center for Integrative Genomics, University of Lausanne, Faculty of Biology and Medicine, Lausanne, Switzerland
| | - Jaime López-Alcalá
- Center for Integrative Genomics, University of Lausanne, Faculty of Biology and Medicine, Lausanne, Switzerland
- Department of Cell Biology, Physiology and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/University of Córdoba/Reina Sofía University Hospital, Córdoba, Spain
| | - Wilson Castro
- Ludwig Institute for Cancer Research, University of Lausanne, Faculty of Biology and Medicine, Lausanne, Switzerland
| | - Nadège Zanou
- Institute of Sport Sciences and Department of Biomedical Sciences, University of Lausanne, Faculty of Biology and Medicine, Lausanne, Switzerland
| | - Laia Martinez-Carreres
- Center for Integrative Genomics, University of Lausanne, Faculty of Biology and Medicine, Lausanne, Switzerland
| | - Katharina Huber
- Center for Integrative Genomics, University of Lausanne, Faculty of Biology and Medicine, Lausanne, Switzerland
| | - Xavier Pascal Berney
- Center for Integrative Genomics, University of Lausanne, Faculty of Biology and Medicine, Lausanne, Switzerland
| | - María M Malagón
- Department of Cell Biology, Physiology and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/University of Córdoba/Reina Sofía University Hospital, Córdoba, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
| | - Catherine Roger
- Center for Integrative Genomics, University of Lausanne, Faculty of Biology and Medicine, Lausanne, Switzerland
| | - Marie-Agnès Berger
- Laboratoire CarMeN, UMR INSERM U1060/INRA U1397, Université Claude Bernard Lyon1, F-69310, Pierre-Bénite, France
| | - Yves Gouriou
- Laboratoire CarMeN, UMR INSERM U1060/INRA U1397, Université Claude Bernard Lyon1, F-69310, Pierre-Bénite, France
| | - Giulia Paone
- Center for Integrative Genomics, University of Lausanne, Faculty of Biology and Medicine, Lausanne, Switzerland
| | - Hector Gallart-Ayala
- Metabolomics Platform, University of Lausanne, Faculty of Biology and Medicine, Rue du Bugnon 19, 1005, Lausanne, Switzerland
| | - George Sflomos
- ISREC-Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Carlos Ronchi
- ISREC-Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Julijana Ivanisevic
- Metabolomics Platform, University of Lausanne, Faculty of Biology and Medicine, Rue du Bugnon 19, 1005, Lausanne, Switzerland
| | - Cathrin Brisken
- ISREC-Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
- The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, UK
| | - Jennifer Rieusset
- Laboratoire CarMeN, UMR INSERM U1060/INRA U1397, Université Claude Bernard Lyon1, F-69310, Pierre-Bénite, France
| | - Melita Irving
- Ludwig Institute for Cancer Research, University of Lausanne, Faculty of Biology and Medicine, Lausanne, Switzerland
| | - Lluis Fajas
- Center for Integrative Genomics, University of Lausanne, Faculty of Biology and Medicine, Lausanne, Switzerland.
- Inserm, Occitanie Méditerranée, Montpellier, France.
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6
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Kim J, Brunetti B, Kumar A, Mangla A, Honda K, Yoshida A. Inhibition of glutaminase elicits senolysis in therapy-induced senescent melanoma cells. Cell Death Dis 2024; 15:902. [PMID: 39695080 DOI: 10.1038/s41419-024-07284-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 11/21/2024] [Accepted: 12/04/2024] [Indexed: 12/20/2024]
Abstract
The cyclin D1-Cyclin-Dependent Kinases 4 and 6 (CDK4/6) complex is crucial for the development of melanoma. We previously demonstrated that targeting CDK4/6 using small molecule inhibitors (CDK4/6i) suppresses BrafV600E melanoma growth in vitro and in vivo through induction of cellular senescence. However, clinical trials investigating CDK4/6i in melanoma have not yielded successful outcomes, underscoring the necessity to enhance the therapeutic efficacy of CDK4/6i. Accumulated research has shown that while senescence initially suppresses cell proliferation, a prolonged state of senescence eventually leads to tumor relapse by altering the tumor microenvironment, suggesting that removal of those senescent cells (in a process referred to as senolysis) is of clinical necessity to facilitate clinical response. We demonstrate that glutaminase 1 (GLS1) expression is specifically upregulated in CDK4/6i-induced senescent BrafV600E melanoma cells. Upregulated GLS1 expression renders BrafV600E melanoma senescent cells vulnerable to GLS1 inhibitor (GLS1i). Furthermore, we demonstrate that this senolytic approach targeting upregulated GLS1 expression is applicable even though those cells developed resistance to the BrafV600E inhibitor vemurafenib, a frequently encountered substantial clinical challenge to treating patients. Thus, this novel senolytic approach may revolutionize current CDK4/6i mediated melanoma treatment if melanoma cells undergo senescence prior to developing resistance to CDK4/6i. Given that we demonstrate that a low dose of vemurafenib induced senescence, which renders BrafV600E melanoma cells susceptible to GLS1i and recent accumulated research shows many cancer cells undergo senescence in response to chemotherapy, radiation, and immunotherapy, this senolytic therapy approach may prove applicable to a wide range of cancer types once senescence and GLS1 expression are induced.
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Affiliation(s)
- Justin Kim
- Department of Dermatology, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, OH, 44106, USA
| | - Bryce Brunetti
- Department of Dermatology, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, OH, 44106, USA
| | - Ayanesh Kumar
- Department of Dermatology, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, OH, 44106, USA
| | - Ankit Mangla
- Department of Hematology and Oncology, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, OH, 44106, USA
| | - Kord Honda
- Department of Dermatology, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, OH, 44106, USA
| | - Akihiro Yoshida
- Department of Dermatology, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, OH, 44106, USA.
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, 44106, USA.
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7
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Yang WC, Wei MF, Lee YH, Huang CS, Kuo SH. Radiosensitizing effects of CDK4/6 inhibitors in hormone receptor-positive and HER2-negative breast cancer mediated downregulation of DNA repair mechanism and NF-κB-signaling pathway. Transl Oncol 2024; 49:102092. [PMID: 39153367 PMCID: PMC11381799 DOI: 10.1016/j.tranon.2024.102092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 07/05/2024] [Accepted: 08/11/2024] [Indexed: 08/19/2024] Open
Abstract
CDK4/6 inhibitors combined with endocrine therapy prolonged survival in hormone receptor (HR)-positive and HER2-negative advanced breast cancer. We investigated whether CDK4/6 inhibitors enhance radiosensitivity and their underlying mechanisms of this subtype of breast cancer. In vitro and in vivo experiments were conducted using two HR-positive and HER2-negative breast cancer cell lines (MCF-7 and T-47D), CDK4/6 inhibitors (ribociclib and palbociclib) and radiotherapy (RT) to assess the biological functions and mechanisms. The radiation-enhancing effect was assessed using clonogenic assays; γH2AX and 53BP1 levels were assessed by immunofluorescence to evaluate DNA damage. The levels of phospho (p)-ERK, c-Myc, and DNA-double strand break (DSB)-related molecules, p-DNA-PKcs, Rad51, and p-ATM, were assessed by western blotting. We used an NF-κB p65 transcription factor assay kit to evaluate NF-κB activity. We evaluated the antitumor effect of the combination of RT and ribociclib through the MCF-7 orthotopic xenograft model. The synergistic effects of combining RT with ribociclib and palbociclib pretreatment were demonstrated by clonogenic assay. CDK4/6 inhibitors synergistically increased the numbers of RT-induced γH2AX and 53BP1, downregulated the expression of p-DNA-PKcs, Rad51 and p-ATM activated by RT, and reduced RT-triggering p-ERK expression, NF-κB activation, and its down-streaming gene, c-Myc. Combined ribociclib and RT reduced the growth of MCF-7 cell xenograft tumors, and downregulated the immunohistochemical expression of p-ERK, p-NF-κB p65, and c-Myc compared to that in the control group. Combining CDK4/6 inhibitors enhanced radiosensitivity of HR-positive and HER2-negative breast cancer cells at least by reducing DNA-DSB repair and weakening the activation of ERK and NF-κB signaling by RT.
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Affiliation(s)
- Wen-Chi Yang
- Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Radiation Oncology, National Taiwan University Cancer Center and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Ming-Feng Wei
- Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yi-Hsuan Lee
- Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chiun-Sheng Huang
- Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Sung-Hsin Kuo
- Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan; Cancer Research Center, National Taiwan University College of Medicine, Taipei, Taiwan.
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8
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Hong T, Hogger AC, Wang D, Pan Q, Gansel J, Engleitner T, Öllinger R, Gschwend JE, Rad R, Nawroth R. CDK4/6 inhibition initiates cell cycle arrest by nuclear translocation of RB and induces a multistep molecular response. Cell Death Discov 2024; 10:453. [PMID: 39461947 PMCID: PMC11513128 DOI: 10.1038/s41420-024-02218-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 09/05/2024] [Accepted: 10/17/2024] [Indexed: 10/28/2024] Open
Abstract
CDK4/6 inhibitors are standard of care in the treatment of metastatic breast cancer. Treatment regimen consists of a combination with endocrine therapy, since their therapeutic efficacy as monotherapy in most clinical trials was rather limited. Thus, understanding the molecular mechanisms that underlie response to therapy might allow for the development of an improved therapy design. We analyzed the response to the CDK4/6 inhibitor palbociclib in bladder cancer cells over a 48-hour time course using RNA sequencing and identified a multi-step mechanism of response. We next translated these results to the molecular mechanism in bladder cancer cells upon PD treatment. The initial step is characterized by translocation of the RB protein into the nucleus by activation of importin α/β, a mechanism that requires the NLS sequence. In parallel, RB is proteolyzed in the cytoplasm, a process regulated by gankyrin and the SCF complex. Only hypophosphorylated RB accumulates in the nucleus, which is an essential step for an efficient therapy response by initiating G1 arrest. This might explain the poor response in RB negative or mutated patients. At later stages during therapy, increased expression of the MiT/TFE protein family leads to lysosomal biogenesis which is essential to maintain this response. Lastly, cancer cells either undergo senescence and apoptosis or develop mechanisms of resistance following CDK4/6 inhibition.
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Affiliation(s)
- Ting Hong
- Department of Urology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Anna C Hogger
- Department of Urology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Dongbiao Wang
- Department of Urology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Qi Pan
- Department of Urology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
- Department of Urology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Julie Gansel
- Department of Urology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Thomas Engleitner
- Institute of Molecular Oncology and Functional Genomics, Technical University of Munich, Munich, Germany
| | - Rupert Öllinger
- Institute of Molecular Oncology and Functional Genomics, Technical University of Munich, Munich, Germany
| | - Jürgen E Gschwend
- Department of Urology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Roland Rad
- Institute of Molecular Oncology and Functional Genomics, Technical University of Munich, Munich, Germany
| | - Roman Nawroth
- Department of Urology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
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9
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Longhurst AD, Wang K, Suresh HG, Ketavarapu M, Ward HN, Jones IR, Narayan V, Hundley FV, Hassan AZ, Boone C, Myers CL, Shen Y, Ramani V, Andrews BJ, Toczyski DP. The PRC2.1 Subcomplex Opposes G1 Progression through Regulation of CCND1 and CCND2. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.18.585604. [PMID: 38562687 PMCID: PMC10983909 DOI: 10.1101/2024.03.18.585604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Progression through the G1 phase of the cell cycle is the most highly regulated step in cellular division. We employed a chemogenetic approach to discover novel cellular networks that regulate cell cycle progression. This approach uncovered functional clusters of genes that altered sensitivity of cells to inhibitors of the G1/S transition. Mutation of components of the Polycomb Repressor Complex 2 rescued proliferation inhibition caused by the CDK4/6 inhibitor palbociclib, but not to inhibitors of S phase or mitosis. In addition to its core catalytic subunits, mutation of the PRC2.1 accessory protein MTF2, but not the PRC2.2 protein JARID2, rendered cells resistant to palbociclib treatment. We found that PRC2.1 (MTF2), but not PRC2.2 (JARID2), was critical for promoting H3K27me3 deposition at CpG islands genome-wide and in promoters. This included the CpG islands in the promoter of the CDK4/6 cyclins CCND1 and CCND2, and loss of MTF2 lead to upregulation of both CCND1 and CCND2. Our results demonstrate a role for PRC2.1, but not PRC2.2, in antagonizing G1 progression in a diversity of cell linages, including CML, breast cancer and immortalized cell lines.
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Affiliation(s)
- Adam D Longhurst
- University of California, San Francisco, San Francisco, CA 94158, USA
- Tetrad Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Kyle Wang
- Department of Molecular Genetics, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada
- The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada
| | - Harsha Garadi Suresh
- Department of Molecular Genetics, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada
| | - Mythili Ketavarapu
- Gladstone Institute for Data Science and Biotechnology, J. David Gladstone Institutes, San Francisco, CA, USA
- Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA
| | - Henry N Ward
- Bioinformatics and Computational Biology Graduate Program, University of Minnesota - Twin Cities Minneapolis MN USA
| | - Ian R Jones
- Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA
- Pharmaceutical Sciences and Pharmacogenomics Graduate Program, University of California
| | - Vivek Narayan
- Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA
| | - Frances V Hundley
- University of California, San Francisco, San Francisco, CA 94158, USA
- Tetrad Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA
- Department of Cell Biology, Blavatnik Institute of Harvard Medical School, Boston, MA 02115, USA
| | - Arshia Zernab Hassan
- Department of Computer Science and Engineering, University of Minnesota - Twin Cities Minneapolis MN USA
| | - Charles Boone
- Department of Molecular Genetics, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada
- The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada
| | - Chad L Myers
- Bioinformatics and Computational Biology Graduate Program, University of Minnesota - Twin Cities Minneapolis MN USA
- Department of Cell Biology, Blavatnik Institute of Harvard Medical School, Boston, MA 02115, USA
| | - Yin Shen
- Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA
- Department of Neurology, University of California, San Francisco, San Francisco, CA, USA
- Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA
| | - Vijay Ramani
- Gladstone Institute for Data Science and Biotechnology, J. David Gladstone Institutes, San Francisco, CA, USA
- Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA
| | - Brenda J Andrews
- The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada
| | - David P Toczyski
- University of California, San Francisco, San Francisco, CA 94158, USA
- Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA
- Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA
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10
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Gao X, Zhao H, Liu J, Wang M, Dai Z, Hao W, Wang Y, Wang X, Zhang M, Liu P, Cheng H, Liu Z. Enzalutamide Sensitizes Castration-Resistant Prostate Cancer to Copper-Mediated Cell Death. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2401396. [PMID: 38859590 PMCID: PMC11321675 DOI: 10.1002/advs.202401396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 05/21/2024] [Indexed: 06/12/2024]
Abstract
Despite the initial efficacy of enzalutamide in castration-resistant prostate cancer (CRPC), inevitable resistance remains a significant challenge. Here, the synergistic induction of copper-dependent cell death (cuproptosis) in CRPC cells is reported by enzalutamide and copper ionophores (elesclomol/disulfiram). Mechanistically, enzalutamide treatment increases mitochondrial dependence in CRPC cells, rendering them susceptible to cuproptosis, as evidenced by specific reversal with the copper chelator tetrathiomolybdate. This susceptibility is characterized by hallmarks of cuproptosis, including lipoylated protein aggregation and iron-sulfur cluster protein instability. Interestingly, the mitochondrial matrix reductase, FDX1, specifically correlates with elesclomol sensitivity, suggesting a potential mechanistic divergence between the two copper ionophores. Notably, this synergistic effect extends beyond in vitro models, demonstrating efficacy in 22Rv1 xenografts, mouse Pten p53 knockout organoids. Importantly, enzalutamide significantly enhances copper ionophore-mediated cytotoxicity in enzalutamide-resistant cells. Collectively, these findings indicate that enzalutamide and copper ionophores synergistically induce cuproptosis, offering a promising therapeutic avenue for CRPC, potentially including enzalutamide-resistant cases.
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Affiliation(s)
- Xiang Gao
- Department of UrologySecond Hospital of Dalian Medical UniversityDalian116023China
| | - Haolin Zhao
- Department of UrologySecond Hospital of Dalian Medical UniversityDalian116023China
| | - Jiao Liu
- Dalian Key Laboratory of Molecular Targeted Cancer TherapyCancer InstituteThe Second Hospital of Dalian Medical UniversityDalian116023China
| | - Min Wang
- Dalian Key Laboratory of Molecular Targeted Cancer TherapyCancer InstituteThe Second Hospital of Dalian Medical UniversityDalian116023China
| | - Zhihong Dai
- Department of UrologySecond Hospital of Dalian Medical UniversityDalian116023China
| | - Wenjun Hao
- Department of UrologySecond Hospital of Dalian Medical UniversityDalian116023China
| | - Yanlong Wang
- Department of UrologySecond Hospital of Dalian Medical UniversityDalian116023China
| | - Xiang Wang
- Department of UrologySecond Hospital of Dalian Medical UniversityDalian116023China
| | - Min Zhang
- Dalian Key Laboratory of Molecular Targeted Cancer TherapyCancer InstituteThe Second Hospital of Dalian Medical UniversityDalian116023China
| | - Pixu Liu
- Dalian Key Laboratory of Molecular Targeted Cancer TherapyCancer InstituteThe Second Hospital of Dalian Medical UniversityDalian116023China
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and TranslationThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhou325000China
| | - Hailing Cheng
- Dalian Key Laboratory of Molecular Targeted Cancer TherapyCancer InstituteThe Second Hospital of Dalian Medical UniversityDalian116023China
| | - Zhiyu Liu
- Department of UrologySecond Hospital of Dalian Medical UniversityDalian116023China
- Liaoning Engineering Research Center of Integrated Precision Diagnosis and Treatment Technology for Urological CancerDalian116023China
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11
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Bhutkar S, Yadav A, Patel H, Barot S, Patel K, Dukhande VV. Synergistic Efficacy of CDK4/6 Inhibitor Abemaciclib and HDAC Inhibitor Panobinostat in Pancreatic Cancer Cells. Cancers (Basel) 2024; 16:2713. [PMID: 39123441 PMCID: PMC11311278 DOI: 10.3390/cancers16152713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 07/09/2024] [Accepted: 07/19/2024] [Indexed: 08/12/2024] Open
Abstract
The current 5-year survival rate of pancreatic cancer is about 12%, making it one of the deadliest malignancies. The rapid metastasis, acquired drug resistance, and poor patient prognosis necessitate better therapeutic strategies for pancreatic ductal adenocarcinoma (PDAC). Multiple studies show that combining chemotherapeutics for solid tumors has been successful. Targeting two distinct emerging hallmarks, such as non-mutational epigenetic changes by panobinostat (Pan) and delayed cell cycle progression by abemaciclib (Abe), inhibits pancreatic cancer growth. HDAC and CDK4/6 inhibitors are effective but are prone to drug resistance and failure as single agents. Therefore, we hypothesized that combining Abe and Pan could synergistically and lethally affect PDAC survival and proliferation. Multiple cell-based assays, enzymatic activity experiments, and flow cytometry experiments were performed to determine the effects of Abe, Pan, and their combination on PDAC cells and human dermal fibroblasts. Western blotting was used to determine the expression of cell cycle, epigenetic, and apoptosis markers. The Abe-Pan combination exhibited excellent efficacy and produced synergistic effects, altering the expression of cell cycle proteins and epigenetic markers. Pan, alone and in combination with Abe, caused apoptosis in pancreatic cancer cells. Abe-Pan co-treatment showed relative safety in normal human dermal fibroblasts. Our novel combination treatment of Abe and Pan shows synergistic effects on PDAC cells. The combination induces apoptosis, shows relative safety, and merits further investigation due to its therapeutic potential in the treatment of PDAC.
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Affiliation(s)
- Shraddha Bhutkar
- Department of Pharmaceutical Sciences, College of Pharmacy & Health Sciences, St. John’s University, Queens, NY 11439, USA
| | - Anjali Yadav
- Department of Pharmaceutical Sciences, College of Pharmacy & Health Sciences, St. John’s University, Queens, NY 11439, USA
| | - Himaxi Patel
- Department of Pharmaceutical Sciences, College of Pharmacy & Health Sciences, St. John’s University, Queens, NY 11439, USA
| | - Shrikant Barot
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Ketan Patel
- Department of Pharmaceutical Sciences, College of Pharmacy & Health Sciences, St. John’s University, Queens, NY 11439, USA
| | - Vikas V. Dukhande
- Department of Pharmaceutical Sciences, College of Pharmacy & Health Sciences, St. John’s University, Queens, NY 11439, USA
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12
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Manohar S, Neurohr GE. Too big not to fail: emerging evidence for size-induced senescence. FEBS J 2024; 291:2291-2305. [PMID: 37986656 DOI: 10.1111/febs.16983] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 10/02/2023] [Accepted: 10/17/2023] [Indexed: 11/22/2023]
Abstract
Cellular senescence refers to a permanent and stable state of cell cycle exit. This process plays an important role in many cellular functions, including tumor suppression. It was first noted that senescence is associated with increased cell size in the early 1960s; however, how this contributes to permanent cell cycle exit was poorly understood until recently. In this review, we discuss new findings that identify increased cell size as not only a consequence but also a cause of permanent cell cycle exit. We highlight recent insights into how increased cell size alters normal cellular physiology and creates homeostatic imbalances that contribute to senescence induction. Finally, we focus on the potential clinical implications of these findings in the context of cell cycle arrest-causing cancer therapeutics and speculate on how tumor cell size changes may impact outcomes in patients treated with these drugs.
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Affiliation(s)
- Sandhya Manohar
- Department of Biology, Institute for Biochemistry, ETH Zürich, Switzerland
| | - Gabriel E Neurohr
- Department of Biology, Institute for Biochemistry, ETH Zürich, Switzerland
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13
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Lewinska M, Zhuravleva E, Satriano L, Martinez MB, Bhatt DK, Oliveira DVNP, Antoku Y, Keggenhoff FL, Castven D, Marquardt JU, Matter MS, Erler JT, Oliveira RC, Aldana BI, Al-Abdulla R, Perugorria MJ, Calvisi DF, Perez LA, Rodrigues PM, Labiano I, Banales JM, Andersen JB. Fibroblast-Derived Lysyl Oxidase Increases Oxidative Phosphorylation and Stemness in Cholangiocarcinoma. Gastroenterology 2024; 166:886-901.e7. [PMID: 38096955 DOI: 10.1053/j.gastro.2023.11.302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 10/24/2023] [Accepted: 11/20/2023] [Indexed: 12/31/2023]
Abstract
BACKGROUND & AIMS Metabolic and transcriptional programs respond to extracellular matrix-derived cues in complex environments, such as the tumor microenvironment. Here, we demonstrate how lysyl oxidase (LOX), a known factor in collagen crosslinking, contributes to the development and progression of cholangiocarcinoma (CCA). METHODS Transcriptomes of 209 human CCA tumors, 143 surrounding tissues, and single-cell data from 30 patients were analyzed. The recombinant protein and a small molecule inhibitor of the LOX activity were used on primary patient-derived CCA cultures to establish the role of LOX in migration, proliferation, colony formation, metabolic fitness, and the LOX interactome. The oncogenic role of LOX was further investigated by RNAscope and in vivo using the AKT/NICD genetically engineered murine CCA model. RESULTS We traced LOX expression to hepatic stellate cells and specifically hepatic stellate cell-derived inflammatory cancer-associated fibroblasts and found that cancer-associated fibroblast-driven LOX increases oxidative phosphorylation and metabolic fitness of CCA, and regulates mitochondrial function through transcription factor A, mitochondrial. Inhibiting LOX activity in vivo impedes CCA development and progression. Our work highlights that LOX alters tumor microenvironment-directed transcriptional reprogramming of CCA cells by facilitating the expression of the oxidative phosphorylation pathway and by increasing stemness and mobility. CONCLUSIONS Increased LOX is driven by stromal inflammatory cancer-associated fibroblasts and correlates with diminished survival of patients with CCA. Modulating the LOX activity can serve as a novel tumor microenvironment-directed therapeutic strategy in bile duct pathologies.
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Affiliation(s)
- Monika Lewinska
- Department of Health and Medical Sciences, Biotech Research and Innovation Center, University of Copenhagen, Copenhagen, Denmark
| | - Ekaterina Zhuravleva
- Department of Health and Medical Sciences, Biotech Research and Innovation Center, University of Copenhagen, Copenhagen, Denmark
| | - Letizia Satriano
- Department of Health and Medical Sciences, Biotech Research and Innovation Center, University of Copenhagen, Copenhagen, Denmark
| | - Marta B Martinez
- Department of Health and Medical Sciences, Biotech Research and Innovation Center, University of Copenhagen, Copenhagen, Denmark
| | - Deepak K Bhatt
- Department of Health and Medical Sciences, Biotech Research and Innovation Center, University of Copenhagen, Copenhagen, Denmark
| | - Douglas V N P Oliveira
- Department of Health and Medical Sciences, Biotech Research and Innovation Center, University of Copenhagen, Copenhagen, Denmark
| | - Yasuko Antoku
- Department of Health and Medical Sciences, Biotech Research and Innovation Center, University of Copenhagen, Copenhagen, Denmark
| | - Friederike L Keggenhoff
- Universitatsklinikum Schleswig-Holstein, Medizinische Klinik I, Campus Lubeck, Lubeck, Germany
| | - Darko Castven
- Universitatsklinikum Schleswig-Holstein, Medizinische Klinik I, Campus Lubeck, Lubeck, Germany
| | - Jens U Marquardt
- Universitatsklinikum Schleswig-Holstein, Medizinische Klinik I, Campus Lubeck, Lubeck, Germany
| | - Matthias S Matter
- Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
| | - Janine T Erler
- Department of Health and Medical Sciences, Biotech Research and Innovation Center, University of Copenhagen, Copenhagen, Denmark
| | - Rui C Oliveira
- Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Blanca I Aldana
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Ruba Al-Abdulla
- Experimental Hepatology and Drug Targeting, Instituto de Investigación Biomédica de Salamanca, University of Salamanca, Salamanca, Spain
| | - Maria J Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country, San Sebastian, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases, Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain; Department of Medicine, Faculty of Medicine and Nursing, University of the Basque Country (Universidad del País Vasco/Euskal Herriko Unibertsitatea), Leioa, Spain
| | - Diego F Calvisi
- University of Regensburg, Institute of Pathology, Regensburg, Germany
| | - Luis Arnes Perez
- Department of Health and Medical Sciences, Biotech Research and Innovation Center, University of Copenhagen, Copenhagen, Denmark
| | - Pedro M Rodrigues
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country, San Sebastian, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases, Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain
| | - Ibone Labiano
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country, San Sebastian, Spain
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country, San Sebastian, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases, Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain; Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain
| | - Jesper B Andersen
- Department of Health and Medical Sciences, Biotech Research and Innovation Center, University of Copenhagen, Copenhagen, Denmark.
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14
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Zhu X, Fu Z, Dutchak K, Arabzadeh A, Milette S, Steinberger J, Morin G, Monast A, Pilon V, Kong T, Adams BN, Prando Munhoz E, Hosein HJB, Fang T, Su J, Xue Y, Rayes R, Sangwan V, Walsh LA, Chen G, Quail DF, Spicer JD, Park M, Dankort D, Huang S. Cotargeting CDK4/6 and BRD4 Promotes Senescence and Ferroptosis Sensitivity in Cancer. Cancer Res 2024; 84:1333-1351. [PMID: 38277141 DOI: 10.1158/0008-5472.can-23-1749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 10/21/2023] [Accepted: 01/17/2024] [Indexed: 01/27/2024]
Abstract
Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are approved for breast cancer treatment and show activity against other malignancies, including KRAS-mutant non-small cell lung cancer (NSCLC). However, the clinical efficacy of CDK4/6 inhibitors is limited due to frequent drug resistance and their largely cytostatic effects. Through a genome-wide cDNA screen, we identified that bromodomain-containing protein 4 (BRD4) overexpression conferred resistance to the CDK4/6 inhibitor palbociclib in KRAS-mutant NSCLC cells. Inhibition of BRD4, either by RNA interference or small-molecule inhibitors, synergized with palbociclib to induce senescence in NSCLC cells and tumors, and the combination prolonged survival in a KRAS-mutant NSCLC mouse model. Mechanistically, BRD4-inhibition enhanced cell-cycle arrest and reactive oxygen species (ROS) accumulation, both of which are necessary for senescence induction; this in turn elevated GPX4, a peroxidase that suppresses ROS-triggered ferroptosis. Consequently, GPX4 inhibitor treatment selectively induced ferroptotic cell death in the senescent cancer cells, resulting in tumor regression. Cotargeting CDK4/6 and BRD4 also promoted senescence and ferroptosis vulnerability in pancreatic and breast cancer cells. Together, these findings reveal therapeutic vulnerabilities and effective combinations to enhance the clinical utility of CDK4/6 inhibitors. SIGNIFICANCE The combination of cytostatic CDK4/6 and BRD4 inhibitors induces senescent cancer cells that are primed for activation of ferroptotic cell death by targeting GPX4, providing an effective strategy for treating cancer.
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Affiliation(s)
- Xianbing Zhu
- Department of Biochemistry, McGill University, Montreal, Quebec, Canada
- Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada
| | - Zheng Fu
- Department of Biochemistry, McGill University, Montreal, Quebec, Canada
- Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada
| | - Kendall Dutchak
- Department of Biology, McGill University, Montreal, Quebec, Canada
| | - Azadeh Arabzadeh
- Department of Biochemistry, McGill University, Montreal, Quebec, Canada
- Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada
| | - Simon Milette
- Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada
- Department of Physiology, McGill University, Montreal, Quebec, Canada
| | - Jutta Steinberger
- Department of Biochemistry, McGill University, Montreal, Quebec, Canada
- Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada
| | - Geneviève Morin
- Department of Biochemistry, McGill University, Montreal, Quebec, Canada
- Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada
| | - Anie Monast
- Department of Biochemistry, McGill University, Montreal, Quebec, Canada
- Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada
| | - Virginie Pilon
- Department of Biochemistry, McGill University, Montreal, Quebec, Canada
- Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada
| | - Tim Kong
- Department of Biochemistry, McGill University, Montreal, Quebec, Canada
- Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada
| | - Bianca N Adams
- Department of Biochemistry, McGill University, Montreal, Quebec, Canada
- Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada
| | - Erika Prando Munhoz
- Department of Biochemistry, McGill University, Montreal, Quebec, Canada
- Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada
| | - Hannah J B Hosein
- Department of Biochemistry, McGill University, Montreal, Quebec, Canada
- Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada
| | - Tianxu Fang
- Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada
- Department of Biomedical Engineering, McGill University, Montreal, Quebec, Canada
| | - Jing Su
- Department of Biochemistry, McGill University, Montreal, Quebec, Canada
- Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada
| | - Yibo Xue
- Department of Biochemistry, McGill University, Montreal, Quebec, Canada
- Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada
| | - Roni Rayes
- Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada
- Department of Surgery, McGill University Health Center, Montreal, Quebec, Canada
| | - Veena Sangwan
- Department of Biochemistry, McGill University, Montreal, Quebec, Canada
- Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada
| | - Logan A Walsh
- Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada
- Department of Human Genetics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
| | - Guojun Chen
- Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada
- Department of Biomedical Engineering, McGill University, Montreal, Quebec, Canada
| | - Daniela F Quail
- Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada
- Department of Physiology, McGill University, Montreal, Quebec, Canada
- Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada
| | - Jonathan D Spicer
- Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada
- Department of Surgery, McGill University Health Center, Montreal, Quebec, Canada
| | - Morag Park
- Department of Biochemistry, McGill University, Montreal, Quebec, Canada
- Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada
| | - David Dankort
- Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada
- Department of Biology, McGill University, Montreal, Quebec, Canada
| | - Sidong Huang
- Department of Biochemistry, McGill University, Montreal, Quebec, Canada
- Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada
- Department of Human Genetics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
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15
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Fan L, Du P, Li Y, Chen X, Liu F, Liu Y, Petrov AM, Li X, Wang Z, Zhao Y. Targeted Liposomes Sensitize Plastic Melanoma to Ferroptosis via Senescence Induction and Coenzyme Depletion. ACS NANO 2024; 18:7011-7023. [PMID: 38390865 DOI: 10.1021/acsnano.3c10142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/24/2024]
Abstract
Ferroptotic cancer therapy has been extensively investigated since the genesis of the ferroptosis concept. However, the therapeutic efficacy of ferroptosis induction in heterogeneous and plastic melanoma has been compromised, because the melanocytic and transitory cell subpopulation is resistant to iron-dependent oxidative stress. Here, we report a phenotype-altering liposomal nanomedicine to enable the ferroptosis-resistant subtypes of melanoma cells vulnerable to lipid peroxidation via senescence induction. The strategy involves the ratiometric coencapsulation of a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor (palbociclib) and a ferroptosis inducer (auranofin) within cRGD peptide-modified targeted liposomes. The two drugs showed a synergistic anticancer effect in the model B16F10 melanoma cells, as evidenced by the combination index analysis (<1). The liposomes could efficiently deliver both drugs into B16F10 cells in a targeted manner. Afterward, the liposomes potently induced the intracellular redox imbalance and lipid peroxidation. Palbociclib significantly provoked cell cycle arrest at the G0/G1 phase, which sensitized auranofin-caused ferroptosis through senescence induction. Meanwhile, palbociclib depleted intracellular glutathione (GSH) and reduced nicotinamide adenine dinucleotide phosphate (NADPH), further boosting ferroptosis. The proof-of-concept was also demonstrated in the B16F10 tumor-bearing mice model. The current work offers a promising ferroptosis-targeting strategy for effectively treating heterogeneous melanoma by manipulating the cellular plasticity.
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Affiliation(s)
- Lanlan Fan
- School of Pharmaceutical Science and Technology, Tianjin Key Laboratory for Modern Drug Delivery and High Efficiency, Tianjin University, Tianjin 300072, China
| | - Panyu Du
- School of Pharmaceutical Science and Technology, Tianjin Key Laboratory for Modern Drug Delivery and High Efficiency, Tianjin University, Tianjin 300072, China
| | - Yaru Li
- School of Pharmaceutical Science and Technology, Tianjin Key Laboratory for Modern Drug Delivery and High Efficiency, Tianjin University, Tianjin 300072, China
| | - Xuefei Chen
- School of Pharmaceutical Science and Technology, Tianjin Key Laboratory for Modern Drug Delivery and High Efficiency, Tianjin University, Tianjin 300072, China
| | - Fang Liu
- School of Pharmaceutical Science and Technology, Tianjin Key Laboratory for Modern Drug Delivery and High Efficiency, Tianjin University, Tianjin 300072, China
| | - Yuning Liu
- School of Pharmaceutical Science and Technology, Tianjin Key Laboratory for Modern Drug Delivery and High Efficiency, Tianjin University, Tianjin 300072, China
| | - Alexey M Petrov
- Kazan State Medical University, 49 Butlerova Street, Kazan, RT 420012, Russia
| | - Xin Li
- School of Pharmaceutical Science and Technology, Tianjin Key Laboratory for Modern Drug Delivery and High Efficiency, Tianjin University, Tianjin 300072, China
| | - Zheng Wang
- School of Pharmaceutical Science and Technology, Tianjin Key Laboratory for Modern Drug Delivery and High Efficiency, Tianjin University, Tianjin 300072, China
| | - Yanjun Zhao
- School of Pharmaceutical Science and Technology, Tianjin Key Laboratory for Modern Drug Delivery and High Efficiency, Tianjin University, Tianjin 300072, China
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16
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Lv S, Yang J, Lin J, Huang X, Zhao H, Zhao C, Yang L. CDK4/6 inhibitors in lung cancer: current practice and future directions. Eur Respir Rev 2024; 33:230145. [PMID: 38355149 PMCID: PMC10865100 DOI: 10.1183/16000617.0145-2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Accepted: 11/11/2023] [Indexed: 02/16/2024] Open
Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide, and ∼85% of lung cancers are classified as nonsmall cell lung cancer (NSCLC). These malignancies can proliferate indefinitely, in part due to dysregulation of the cell cycle and the resulting abnormal cell growth. The specific activation of cyclin-dependent kinases 4 and 6 (CDK4/6) is closely linked to tumour proliferation. Approximately 80% of human tumours exhibit abnormalities in the cyclin D-CDK4/6-INK4-RB pathway. Specifically, CDK4/6 inhibitors either as monotherapy or combination therapy have been investigated in pre-clinical and clinical studies for the treatment of NSCLC, and promising results have been achieved. This review article focuses on research regarding the use of CDK4/6 inhibitors in NSCLC, including the characteristics and mechanisms of action of approved drugs and progress of pre-clinical and clinical research.
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Affiliation(s)
- Shuoshuo Lv
- The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
- The Institute of Life Sciences, Wenzhou University, Wenzhou, China
- These authors contributed equally to this work
| | - Jie Yang
- The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
- The Institute of Life Sciences, Wenzhou University, Wenzhou, China
- These authors contributed equally to this work
| | - Jiayuh Lin
- Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD, USA
| | - Xiaoying Huang
- The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Haiyang Zhao
- The Institute of Life Sciences, Wenzhou University, Wenzhou, China
| | - Chengguang Zhao
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Lehe Yang
- The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
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17
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Adamopoulos C, Cave DD, Papavassiliou AG. Inhibition of the RAF/MEK/ERK Signaling Cascade in Pancreatic Cancer: Recent Advances and Future Perspectives. Int J Mol Sci 2024; 25:1631. [PMID: 38338909 PMCID: PMC10855714 DOI: 10.3390/ijms25031631] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 01/22/2024] [Accepted: 01/26/2024] [Indexed: 02/12/2024] Open
Abstract
Pancreatic cancer represents a formidable challenge in oncology, primarily due to its aggressive nature and limited therapeutic options. The prognosis of patients with pancreatic ductal adenocarcinoma (PDAC), the main form of pancreatic cancer, remains disappointingly poor with a 5-year overall survival of only 5%. Almost 95% of PDAC patients harbor Kirsten rat sarcoma virus (KRAS) oncogenic mutations. KRAS activates downstream intracellular pathways, most notably the rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling axis. Dysregulation of the RAF/MEK/ERK pathway is a crucial feature of pancreatic cancer and therefore its main components, RAF, MEK and ERK kinases, have been targeted pharmacologically, largely by small-molecule inhibitors. The recent advances in the development of inhibitors not only directly targeting the RAF/MEK/ERK pathway but also indirectly through inhibition of its regulators, such as Src homology-containing protein tyrosine phosphatase 2 (SHP2) and Son of sevenless homolog 1 (SOS1), provide new therapeutic opportunities. Moreover, the discovery of allele-specific small-molecule inhibitors against mutant KRAS variants has brought excitement for successful innovations in the battle against pancreatic cancer. Herein, we review the recent advances in targeted therapy and combinatorial strategies with focus on the current preclinical and clinical approaches, providing critical insight, underscoring the potential of these efforts and supporting their promise to improve the lives of patients with PDAC.
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Affiliation(s)
- Christos Adamopoulos
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Donatella Delle Cave
- Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’, CNR, 80131 Naples, Italy
| | - Athanasios G. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
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18
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Lee JH, Lee JD, Paulson K, Voillet V, Berndt A, Church C, Lachance K, Park SY, Yamamoto NK, Cromwell EA, Gottardo R, Chapuis AG, Nghiem P. Enhancing immunogenic responses through CDK4/6 and HIF2α inhibition in Merkel cell carcinoma. Heliyon 2024; 10:e23521. [PMID: 38173534 PMCID: PMC10761584 DOI: 10.1016/j.heliyon.2023.e23521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 11/19/2023] [Accepted: 12/05/2023] [Indexed: 01/05/2024] Open
Abstract
Approximately 50% of Merkel cell carcinoma (MCC) patients facing this highly aggressive skin cancer initially respond positively to PD-1-based immunotherapy. Nevertheless, the recurrence of MCC post-immunotherapy emphasizes the pressing need for more effective treatments. Recent research has highlighted Cyclin-dependent kinases 4 and 6 (CDK4/6) as pivotal cell cycle regulators gaining prominence in cancer studies. This study reveals that the CDK4/6 inhibitor, palbociclib can enhance PD-L1 gene transcription and surface expression in MCC cells by activating HIF2α. Inhibiting HIF2α with TC-S7009 effectively counteracts palbociclib-induced PD-L1 transcription and significantly intensifies cell death in MCC. Simultaneously, co-targeting CDK4/6 and HIF2α boosts ROS levels while suppressing SLC7A11, a key regulator of cellular redox balance, promoting ferroptosis- a form of immunogenic cell death linked to iron. Considering the rising importance of immunogenic cell death in immunotherapy, this strategy holds promise for improving future MCC treatments, markedly increasing immunogenic cell death various across various MCC cell lines, thus advancing cancer immunotherapy.
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Affiliation(s)
- Jung Hyun Lee
- Department of Dermatology, School of Medicine, University of Washington, Seattle, WA, USA
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA
| | - Justin Daho Lee
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA
| | - Kelly Paulson
- Department of Dermatology, School of Medicine, University of Washington, Seattle, WA, USA
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Seattle Cancer Care Alliance, Seattle, WA, USA
| | - Valentin Voillet
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Andre Berndt
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA
| | - Candice Church
- Department of Dermatology, School of Medicine, University of Washington, Seattle, WA, USA
| | - Kristina Lachance
- Department of Dermatology, School of Medicine, University of Washington, Seattle, WA, USA
| | - Song Y. Park
- Department of Dermatology, School of Medicine, University of Washington, Seattle, WA, USA
| | - Naomi K. Yamamoto
- Medical Scientist Training Program, University of Washington, Seattle, WA, USA
| | | | - Raphael Gottardo
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Aude G. Chapuis
- Department of Dermatology, School of Medicine, University of Washington, Seattle, WA, USA
- Seattle Cancer Care Alliance, Seattle, WA, USA
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Paul Nghiem
- Department of Dermatology, School of Medicine, University of Washington, Seattle, WA, USA
- Seattle Cancer Care Alliance, Seattle, WA, USA
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
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19
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Ziegler DV, Parashar K, Fajas L. Beyond cell cycle regulation: The pleiotropic function of CDK4 in cancer. Semin Cancer Biol 2024; 98:51-63. [PMID: 38135020 DOI: 10.1016/j.semcancer.2023.12.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 11/02/2023] [Accepted: 12/17/2023] [Indexed: 12/24/2023]
Abstract
CDK4, along with its regulatory subunit, cyclin D, drives the transition from G1 to S phase, during which DNA replication and metabolic activation occur. In this canonical pathway, CDK4 is essentially a transcriptional regulator that acts through phosphorylation of retinoblastoma protein (RB) and subsequent activation of the transcription factor E2F, ultimately triggering the expression of genes involved in DNA synthesis and cell cycle progression to S phase. In this review, we focus on the newly reported functions of CDK4, which go beyond direct regulation of the cell cycle. In particular, we describe the extranuclear roles of CDK4, including its roles in the regulation of metabolism, cell fate, cell dynamics and the tumor microenvironment. We describe direct phosphorylation targets of CDK4 and decipher how CDK4 influences these physiological processes in the context of cancer.
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Affiliation(s)
- Dorian V Ziegler
- Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
| | - Kanishka Parashar
- Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
| | - Lluis Fajas
- Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland; INSERM, Montpellier, France.
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20
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Danishevich A, Bilyalov A, Nikolaev S, Khalikov N, Isaeva D, Levina Y, Makarova M, Nemtsova M, Chernevskiy D, Sagaydak O, Baranova E, Vorontsova M, Byakhova M, Semenova A, Galkin V, Khatkov I, Gadzhieva S, Bodunova N. CDKN2A Gene Mutations: Implications for Hereditary Cancer Syndromes. Biomedicines 2023; 11:3343. [PMID: 38137564 PMCID: PMC10741544 DOI: 10.3390/biomedicines11123343] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Revised: 12/10/2023] [Accepted: 12/12/2023] [Indexed: 12/24/2023] Open
Abstract
Malignant neoplasms, including pancreatic cancer and melanoma, are major global health challenges. This study investigates melanoma pancreatic syndrome, a rare hereditary tumor syndrome associated with CDKN2A gene mutations. CDKN2A mutations contribute to a lifetime risk of melanoma ranging from 28% to 67%. This study reports the clinical features of six individuals with CDKN2A mutations and identifies recurrent alterations such as c.307_308del, c.159G>C and c.71G>C. It highlights the need for CDKN2A mutation testing in suspected cases of familial atypical multiple mole melanoma. Clinically significant variants show associations with melanoma and pancreatic cancer. The challenges of treating individuals with CDKN2A mutations are discussed, and the lack of specific targeted therapies is highlighted. Preclinical studies suggest a potential benefit of CDK4/6 inhibitors, although clinical trials show mixed results. This study underscores the importance of continued research into improved diagnostic and therapeutic strategies to address the complexities of hereditary cancer syndromes.
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Affiliation(s)
- Anastasiia Danishevich
- SBHI Moscow Clinical Scientific Center Named after Loginov MHD, 111123 Moscow, Russia (N.K.); (D.I.)
| | - Airat Bilyalov
- SBHI Moscow Clinical Scientific Center Named after Loginov MHD, 111123 Moscow, Russia (N.K.); (D.I.)
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
| | - Sergey Nikolaev
- SBHI Moscow Clinical Scientific Center Named after Loginov MHD, 111123 Moscow, Russia (N.K.); (D.I.)
| | - Nodirbec Khalikov
- SBHI Moscow Clinical Scientific Center Named after Loginov MHD, 111123 Moscow, Russia (N.K.); (D.I.)
| | - Daria Isaeva
- SBHI Moscow Clinical Scientific Center Named after Loginov MHD, 111123 Moscow, Russia (N.K.); (D.I.)
| | - Yuliya Levina
- SBHI Moscow Clinical Scientific Center Named after Loginov MHD, 111123 Moscow, Russia (N.K.); (D.I.)
| | - Maria Makarova
- LLC Evogen, 115191 Moscow, Russia
- Federal State Budgetary Institution Russian Scientific Center of Roentgenoradiology, Ministry of Healthcare of the Russian Federation, 117997 Moscow, Russia
| | - Marina Nemtsova
- LLC Evogen, 115191 Moscow, Russia
- Research Centre for Medical Genetics of N.P. Bochkov, 115522 Moscow, Russia
- Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov, Ministry of Health of Russian Federation, 119991 Moscow, Russia
| | - Denis Chernevskiy
- LLC Evogen, 115191 Moscow, Russia
- FSBEI HE “Privolzhsky Research Medical University”, Ministry of Health of Russian Federation, 603950 Nizhny Novgorod, Russia
| | - Olesya Sagaydak
- LLC Evogen, 115191 Moscow, Russia
- Federal State Budgetary Institution National Medical Research Center of Cardiology Named after Academician E.I. Chazov, Ministry of Health of the Russian Federation, 121552 Moscow, Russia
| | - Elena Baranova
- LLC Evogen, 115191 Moscow, Russia
- Russian Medical Academy of Continuous Professional Education, Russia, 125993 Moscow, Russia
| | - Maria Vorontsova
- Faculty of Medicine, Lomonosov Moscow State University, 119991 Moscow, Russia
- The National Medical Research Center for Endocrinology, 117292 Moscow, Russia
| | - Mariya Byakhova
- Moscow Healthcare Department, Moscow State Budgetary Healthcare Institution Moscow City Oncological Hospital No. 1, 117152 Moscow, Russia
| | - Anna Semenova
- Moscow Healthcare Department, Moscow State Budgetary Healthcare Institution Moscow City Oncological Hospital No. 1, 117152 Moscow, Russia
| | - Vsevolod Galkin
- Moscow Healthcare Department, Moscow State Budgetary Healthcare Institution Moscow City Oncological Hospital No. 1, 117152 Moscow, Russia
| | - Igor Khatkov
- SBHI Moscow Clinical Scientific Center Named after Loginov MHD, 111123 Moscow, Russia (N.K.); (D.I.)
| | | | - Natalia Bodunova
- SBHI Moscow Clinical Scientific Center Named after Loginov MHD, 111123 Moscow, Russia (N.K.); (D.I.)
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21
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Zhao T, Jiang T, Li X, Chang S, Sun Q, Kong F, Kong X, Wei F, He J, Hao J, Xie K. Nuclear GRP78 Promotes Metabolic Reprogramming and Therapeutic Resistance in Pancreatic Ductal Adenocarcinoma. Clin Cancer Res 2023; 29:5183-5195. [PMID: 37819952 DOI: 10.1158/1078-0432.ccr-23-1143] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 08/04/2023] [Accepted: 10/06/2023] [Indexed: 10/13/2023]
Abstract
PURPOSE Stromal fibrosis limits nutritional supply and disarrays metabolism in pancreatic cancer (PDA, pancreatic ductal adenocarcinoma). Understanding of the molecular basis underlying metabolic cues would improve PDA management. The current study determined the interaction between glucose-regulated proteins 78 (GRP78) and hypoxia-inducible factor 1α (HIF-1α) and its mechanistic roles underlying PDA response to oxygen and glucose restrains. EXPERIMENTAL DESIGN Gene expression and its association with clinicopathologic characteristics of patients with PDA and mouse models were analyzed using IHC. Protein expression and their regulation were measured by Western blot and immunoprecipitation analyses. Protein interactions were determined using gain- and loss-of-function assays and molecular methods, including chromatin immunoprecipitation, co-immunoprecipitation, and dual luciferase reporter. RESULTS There was concomitant overexpression of both GRP78 and HIF-1α in human and mouse PDA tissues and cells. Glucose deprivation increased the expression of GRP78 and HIF-1α, particularly colocalization in nucleus. Induction of HIF-1α expression by glucose deprivation in PDA cells depended on the expression of and its own interaction with GRP78. Mechanistically, increased expression of both HIF-1α and LDHA under glucose deprivation was caused by the direct binding of GRP78 and HIF-1α protein complexes to the promoters of HIF-1α and LDHA genes and transactivation of their transcriptional activity. CONCLUSIONS Protein complex of GRP78 and HIF-1α directly binds to HIF-1α own promoter and LDHA promoter, enhances the transcription of both HIF-1α and LDHA, whereas glucose deprivation increases GRP78 expression and further enhances HIF-1α and LDHA transcription. Therefore, crosstalk and integration of hypoxia- and hypoglycemia-responsive signaling critically impact PDA metabolic reprogramming and therapeutic resistance.
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Affiliation(s)
- Tiansuo Zhao
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Tingting Jiang
- Center for Pancreatic Cancer Research, The South China University of Technology School of Medicine, Guangzhou, China
| | - Xiaojia Li
- Center for Pancreatic Cancer Research, The South China University of Technology School of Medicine, Guangzhou, China
| | - Shaofei Chang
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Qihui Sun
- Center for Pancreatic Cancer Research, The South China University of Technology School of Medicine, Guangzhou, China
| | - Fanyang Kong
- Department of Gastroenterology, Changhai Hospital, Shanghai, China
| | - Xiangyu Kong
- Department of Gastroenterology, Changhai Hospital, Shanghai, China
| | - Fang Wei
- Institute of Digestive Diseases, Guangzhou First People's Hospital and The Second Affiliated Hospital, The South China University of Technology School of Medicine, Guangzhou, China
| | - Jie He
- Institute of Digestive Diseases, Guangzhou First People's Hospital and The Second Affiliated Hospital, The South China University of Technology School of Medicine, Guangzhou, China
| | - Jihui Hao
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Keping Xie
- Center for Pancreatic Cancer Research, The South China University of Technology School of Medicine, Guangzhou, China
- Institute of Digestive Diseases, Guangzhou First People's Hospital and The Second Affiliated Hospital, The South China University of Technology School of Medicine, Guangzhou, China
- The South China University of Technology Comprehensive Cancer Center, Guangzhou, China
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22
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Liu C, Ma G, Zhang J, Cheng J, Yang Z, Song S. 18F-FES and 18F-FDG PET/CT imaging as a predictive biomarkers for metastatic breast cancer patients undergoing cyclin-dependent 4/6 kinase inhibitors with endocrine treatment. Ann Nucl Med 2023; 37:675-684. [PMID: 37787851 DOI: 10.1007/s12149-023-01871-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 09/19/2023] [Indexed: 10/04/2023]
Abstract
OBJECTIVE The aim of this study was to investigate the potential value of dual tracers 18F-FDG and 18F-FES PET/CT in predicting response to Cyclin-Dependent 4/6 Kinase (CDK4/6) inhibitors combined with endocrine therapy for metastatic estrogen receptor (ER)-positive breast cancer patients. METHODS This retrospective study enrolled 38 ER-positive metastatic breast cancer patients from our center who underwent both 18F-FDG and 18F-FES PET/CT scans within 1 month before CDK4/6 inhibitors combined with endocrine therapy. The extracted parameters comprised the maximum standardized uptake value (SUVmax) for both FDG and FES PET, as well as the ratio between FES and FDG SUVmax. Each parameter was dichotomized based on its median threshold. The primary endpoint was progression-free survival (PFS), which was estimated using the Kaplan-Meier method and compared by the log-rank test. RESULTS After a median follow-up of 15.6 months, progressive disease was observed in 23 out of 38 patients, and the median PFS for the whole cohort was 21.0 months [95% confidence interval (CI) 12.7-29.3]. FES and FDG PET identified 6 patients (15.8%) with FES-negative lesions, suggesting ER heterogeneity in metastatic lesions. The median PFS of these patients was only 5.3 months (95% CI 1.7-8.9), which was substantially shorter than that of patients with 100% FES-positive lesions (median PFS 22.9 months, 95% CI 17.1-28.7, P < 0.001). Patients with 100% FES-positive lesions who had high FES/FDG showed significantly shorter PFS compared to those with low FES/FDG (14.9 vs. 30.5 months, P = 0.003). CONCLUSIONS This study shows that FDG and FES PET imaging may serve as valuable tools for patient selection in the context of CDK4/6 inhibitor therapy combined with endocrine treatment, and have the potential to function as prognostic biomarkers.
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Affiliation(s)
- Cheng Liu
- Department of Nuclear Medicine, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, 4365 Kangxin Road, Shanghai, 201321, China
- Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, 201321, China
- Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, 201321, China
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Shanghai Institute of Medical Imaging, Fudan University, Shanghai, 200032, China
| | - Guang Ma
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Jiangang Zhang
- Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, 201321, China
- Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, 201321, China
- Department of Nuclear Medicine, Shanghai Proton and Heavy Ion Center, Shanghai, 201321, China
| | - Jingyi Cheng
- Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, 201321, China
- Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, 201321, China
- Department of Nuclear Medicine, Shanghai Proton and Heavy Ion Center, Shanghai, 201321, China
| | - Zhongyi Yang
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
| | - Shaoli Song
- Department of Nuclear Medicine, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, 4365 Kangxin Road, Shanghai, 201321, China.
- Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, 201321, China.
- Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, 201321, China.
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
- Shanghai Institute of Medical Imaging, Fudan University, Shanghai, 200032, China.
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23
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Crozier L, Foy R, Adib R, Kar A, Holt JA, Pareri AU, Valverde JM, Rivera R, Weston WA, Wilson R, Regnault C, Whitfield P, Badonyi M, Bennett LG, Vernon EG, Gamble A, Marsh JA, Staples CJ, Saurin AT, Barr AR, Ly T. CDK4/6 inhibitor-mediated cell overgrowth triggers osmotic and replication stress to promote senescence. Mol Cell 2023; 83:4062-4077.e5. [PMID: 37977118 DOI: 10.1016/j.molcel.2023.10.016] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 07/10/2023] [Accepted: 10/16/2023] [Indexed: 11/19/2023]
Abstract
Abnormal increases in cell size are associated with senescence and cell cycle exit. The mechanisms by which overgrowth primes cells to withdraw from the cell cycle remain unknown. We address this question using CDK4/6 inhibitors, which arrest cells in G0/G1 and are licensed to treat advanced HR+/HER2- breast cancer. We demonstrate that CDK4/6-inhibited cells overgrow during G0/G1, causing p38/p53/p21-dependent cell cycle withdrawal. Cell cycle withdrawal is triggered by biphasic p21 induction. The first p21 wave is caused by osmotic stress, leading to p38- and size-dependent accumulation of p21. CDK4/6 inhibitor washout results in some cells entering S-phase. Overgrown cells experience replication stress, resulting in a second p21 wave that promotes cell cycle withdrawal from G2 or the subsequent G1. We propose that the levels of p21 integrate signals from overgrowth-triggered stresses to determine cell fate. This model explains how hypertrophy can drive senescence and why CDK4/6 inhibitors have long-lasting effects in patients.
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Affiliation(s)
- Lisa Crozier
- Cellular and Systems Medicine, Jacqui Wood Cancer Centre, School of Medicine, University of Dundee, Dundee, UK
| | - Reece Foy
- Cellular and Systems Medicine, Jacqui Wood Cancer Centre, School of Medicine, University of Dundee, Dundee, UK
| | - Rozita Adib
- MRC Laboratory of Medical Sciences, London, UK
| | - Ananya Kar
- Molecular Cell and Developmental Biology, School of Life Sciences, Dundee, UK
| | | | - Aanchal U Pareri
- Cellular and Systems Medicine, Jacqui Wood Cancer Centre, School of Medicine, University of Dundee, Dundee, UK
| | - Juan M Valverde
- Cellular and Systems Medicine, Jacqui Wood Cancer Centre, School of Medicine, University of Dundee, Dundee, UK
| | - Rene Rivera
- Molecular Cell and Developmental Biology, School of Life Sciences, Dundee, UK
| | | | - Rona Wilson
- Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UK
| | - Clement Regnault
- Glasgow Polyomics College of Medical, Veterinary, and Life Sciences, University of Glasgow, UK
| | - Phil Whitfield
- Glasgow Polyomics College of Medical, Veterinary, and Life Sciences, University of Glasgow, UK
| | - Mihaly Badonyi
- MRC Human Genetics Unit, University of Edinburgh, Edinburgh, UK
| | - Laura G Bennett
- North West Cancer Research Institute, School of Medical and Health Sciences, Brambell Building, Deiniol Rd, Bangor LL57 2UW, UK
| | - Ellen G Vernon
- North West Cancer Research Institute, School of Medical and Health Sciences, Brambell Building, Deiniol Rd, Bangor LL57 2UW, UK
| | - Amelia Gamble
- North West Cancer Research Institute, School of Medical and Health Sciences, Brambell Building, Deiniol Rd, Bangor LL57 2UW, UK
| | - Joseph A Marsh
- MRC Human Genetics Unit, University of Edinburgh, Edinburgh, UK
| | - Christopher J Staples
- North West Cancer Research Institute, School of Medical and Health Sciences, Brambell Building, Deiniol Rd, Bangor LL57 2UW, UK
| | - Adrian T Saurin
- Cellular and Systems Medicine, Jacqui Wood Cancer Centre, School of Medicine, University of Dundee, Dundee, UK.
| | - Alexis R Barr
- MRC Laboratory of Medical Sciences, London, UK; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK.
| | - Tony Ly
- Molecular Cell and Developmental Biology, School of Life Sciences, Dundee, UK; Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UK; Glasgow Polyomics College of Medical, Veterinary, and Life Sciences, University of Glasgow, UK.
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24
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Wang M, Liu J, Liao X, Yi Y, Xue Y, Yang L, Cheng H, Liu P. The SGK3-Catalase antioxidant signaling axis drives cervical cancer growth and therapy resistance. Redox Biol 2023; 67:102931. [PMID: 37866161 PMCID: PMC10623367 DOI: 10.1016/j.redox.2023.102931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 10/05/2023] [Accepted: 10/10/2023] [Indexed: 10/24/2023] Open
Abstract
Cancer cells frequently exhibit aberrant redox homeostasis and adaptation to oxidative stress. Hence abrogation of redox adaptation in cancer cells can be exploited for therapeutic benefit. Here we report SGK3 functions as an anti-oxidative factor to promote cell growth and drug resistance in cervical cancers harboring PIK3CA helical domain mutations. Mechanistically, SGK3 is activated upon oxidative stress and exerts anti-ROS activity by stabilizing and activating the antioxidant enzyme catalase. SGK3 interacts with and phosphorylates catalase, promoting its tetrameric state and activity. Meanwhile, SGK3 phosphorylates GSK3β and protects catalase from GSK3β-β-TrCP mediated ubiquitination and proteasomal degradation. Furthermore, SGK3 inhibition not only potentiates CDK4/6 inhibitor Palbociclib-mediated cytotoxicity, but also overcomes cisplatin resistance through ROS-mediated mechanisms. These data uncover the role of SGK3 in maintaining redox homeostasis and suggest that the SGK3-catalase antioxidant signaling axis may be therapeutically targeted to improve treatment efficacy for cervical cancers carrying PIK3CA helical domain mutations.
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Affiliation(s)
- Min Wang
- Cancer Institute, The Second Hospital of Dalian Medical University, Dalian Key Laboratory of Molecular Targeted Cancer Therapy, Dalian, China
| | - Jiannan Liu
- Cancer Institute, The Second Hospital of Dalian Medical University, Dalian Key Laboratory of Molecular Targeted Cancer Therapy, Dalian, China
| | - Xingming Liao
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning Province, China
| | - Yasong Yi
- Cancer Institute, The Second Hospital of Dalian Medical University, Dalian Key Laboratory of Molecular Targeted Cancer Therapy, Dalian, China
| | - Yijue Xue
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning Province, China
| | - Ling Yang
- School of Pharmacy, Zunyi Medical University, Zunyi, China; Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China; Department of Pharmacology, Key Laboratory of Basic Pharmacology of Guizhou Province, Zunyi Medical University, Zunyi, China.
| | - Hailing Cheng
- Cancer Institute, The Second Hospital of Dalian Medical University, Dalian Key Laboratory of Molecular Targeted Cancer Therapy, Dalian, China.
| | - Pixu Liu
- Cancer Institute, The Second Hospital of Dalian Medical University, Dalian Key Laboratory of Molecular Targeted Cancer Therapy, Dalian, China; Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning Province, China; Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China.
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25
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Tang H, Ge Y, You T, Li X, Wang Y, Cheng Y, Bai C. A real-world analysis of trametinib in combination with hydroxychloroquine or CDK4/6 inhibitor as third- or later-line therapy in metastatic pancreatic adenocarcinoma. BMC Cancer 2023; 23:958. [PMID: 37817078 PMCID: PMC10563303 DOI: 10.1186/s12885-023-11464-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 09/28/2023] [Indexed: 10/12/2023] Open
Abstract
BACKGROUND There are no standard third-line treatment options for metastatic pancreatic ductal adenocarcinoma (mPDAC). Trametinib in combination with hydroxychloroquine (HCQ) or CDK4/6 inhibitors for pancreatic adenocarcinoma showed promising efficacy in preclinical studies. However, the regimens have not been well examined in patients with mPDAC. METHODS Patients with mPDAC who received the combination of trametinib and HCQ or CDK4/6 inhibitors as third- or later-line therapy were reviewed. The efficacy and prognosis were further analyzed. RESULTS A total of 13 mPDAC patients were enrolled, of whom 8 and 5 patients were treated with trametinib plus HCQ or a CDK4/6 inhibitor (palbociclib or abemaciclib), respectively. All enrolled patients had either KRAS G12D or G12V mutations and had received a median of 3 prior lines of therapy (range, 2-6). The median trametinib treatment duration was 1.4 months. Of the 10 patients with measurable disease, only 1 patient achieved stable disease, and the remaining patients had progressive disease. Moreover, in patients treated with trametinib plus HCQ and a CDK4/6 inhibitor, the median progression-free survival was 2.0 and 2.8 months, respectively, and the median overall survival was 4.2 and 4.7 months, respectively. Moreover, 5 (50%) patients experienced grade 3-4 adverse events in 10 patients with available safety data. CONCLUSIONS The combination of trametinib and HCQ or CDK4/6 inhibitors may not be an effective later-line treatment for mPDAC, and the current preliminary findings need to be confirmed by other studies with larger sample sizes.
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Affiliation(s)
- Hui Tang
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yuping Ge
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Tingting You
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xiaoyuan Li
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yingyi Wang
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yuejuan Cheng
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
| | - Chunmei Bai
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
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26
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Gomes I, Abreu C, Costa L, Casimiro S. The Evolving Pathways of the Efficacy of and Resistance to CDK4/6 Inhibitors in Breast Cancer. Cancers (Basel) 2023; 15:4835. [PMID: 37835528 PMCID: PMC10571967 DOI: 10.3390/cancers15194835] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 09/28/2023] [Accepted: 09/30/2023] [Indexed: 10/15/2023] Open
Abstract
The approval of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) has remarkably improved the survival outcomes of patients with advanced hormone receptor-positive (HR+) breast cancer (BC), becoming the new standard of care treatment in these patients. Despite the efficacy of this therapeutic combination, intrinsic and acquired resistance inevitably occurs and represents a major clinical challenge. Several mechanisms associated with resistance to CDK4/6i have been identified, including both cell cycle-related and cell cycle-nonspecific mechanisms. This review discusses new insights underlying the mechanisms of action of CDK4/6i, which are more far-reaching than initially thought, and the currently available evidence of the mechanisms of resistance to CDK4/6i in BC. Finally, it highlights possible treatment strategies to improve CDK4/6i efficacy, summarizing the most relevant clinical data on novel combination therapies involving CDK4/6i.
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Affiliation(s)
- Inês Gomes
- Luis Costa Lab, Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Universidade de Lisboa, 1649-028 Lisbon, Portugal;
| | - Catarina Abreu
- Oncology Division, Hospital de Santa Maria—Centro Hospitalar Universitário Lisboa Norte, 1649-028 Lisbon, Portugal;
| | - Luis Costa
- Luis Costa Lab, Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Universidade de Lisboa, 1649-028 Lisbon, Portugal;
- Oncology Division, Hospital de Santa Maria—Centro Hospitalar Universitário Lisboa Norte, 1649-028 Lisbon, Portugal;
| | - Sandra Casimiro
- Luis Costa Lab, Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Universidade de Lisboa, 1649-028 Lisbon, Portugal;
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27
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Chiorean EG, Picozzi V, Li C, Peeters M, Maurel J, Singh J, Golan T, Blanc J, Chapman SC, Hussain AM, Johnston EL, Hochster HS. Efficacy and safety of abemaciclib alone and with PI3K/mTOR inhibitor LY3023414 or galunisertib versus chemotherapy in previously treated metastatic pancreatic adenocarcinoma: A randomized controlled trial. Cancer Med 2023; 12:20353-20364. [PMID: 37840530 PMCID: PMC10652308 DOI: 10.1002/cam4.6621] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 08/07/2023] [Accepted: 09/30/2023] [Indexed: 10/17/2023] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinomas (PDAC) are characterized by frequent cell cycle pathways aberrations. This study evaluated safety and efficacy of abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, as monotherapy or in combination with PI3K/mTOR dual inhibitor LY3023414 or TGFβ inhibitor galunisertib versus standard of care (SOC) chemotherapy in patients with pretreated metastatic PDAC. METHODS This Phase 2 open-label study enrolled patients with metastatic PDAC who progressed after 1-2 prior therapies. Patients were enrolled in a safety lead-in (abemaciclib plus galunisertib) followed by a 2-stage randomized design. Stage 1 randomization was planned 1:1:1:1 for abemaciclib, abemaciclib plus LY3023414, abemaciclib plus galunisertib, or SOC gemcitabine or capecitabine. Advancing to Stage 2 required a disease control rate (DCR) difference ≥0 in abemaciclib-containing arms versus SOC. Primary objectives for Stages 1 and 2 were DCR and progression-free survival (PFS), respectively. Secondary objectives included response rate, overall survival, safety, and pharmacokinetics. RESULTS One hundred and six patients were enrolled. Abemaciclib plus galunisertib did not advance to Stage 1 for reasons unrelated to safety or efficacy. Stage 1 DCR was 15.2% with abemaciclib monotherapy, 12.1% with abemaciclib plus LY3023414, and 36.4% with SOC. Median PFS was 1.7 months (95% CI: 1.4-1.8), 1.8 months (95% CI: 1.3-1.9), and 3.3 months (95% CI: 1.1-5.7), respectively. No arms advanced to Stage 2. No new safety signals were identified. CONCLUSION In patients with pretreated metastatic PDAC, abemaciclib-based therapy did not improve DCRs or PFS compared with SOC chemotherapy. No treatment arms advanced to Stage 2. Abemaciclib remains investigational in patients with PDAC.
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Affiliation(s)
- E. Gabriela Chiorean
- University of Washington School of MedicineSeattleWashingtonUSA
- Fred Hutchinson Cancer CenterSeattleWashingtonUSA
| | - Vincent Picozzi
- Virginia Mason Hospital and Medical CenterSeattleWashingtonUSA
| | - Chung‐Pin Li
- Division of Clinical Skills Training, Department of Medical EducationTaipei Veterans General HospitalTaipeiTaiwan
- Division of Gastroenterology and Hepatology, Department of MedicineTaipei Veterans General HospitalTaipeiTaiwan
- Therapeutic and Research Center of Pancreatic CancerTaipei Veterans General HospitalTaipeiTaiwan
- School of Medicine, College of MedicineNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
| | - Marc Peeters
- Department of OncologyAntwerp University HospitalAntwerpBelgium
- Department of Oncology, Faculty of Medicine and Health SciencesUniversity of AntwerpAntwerpBelgium
| | - Joan Maurel
- Medical Oncology Department, Hospital Clinic of Barcelona, Translational Genomics and Targeted Therapeutics in Solid Tumors Group, IDIBAPSUniversity of BarcelonaBarcelonaSpain
| | - Jaswinder Singh
- Sarah Cannon Cancer Institute at Research Medical CenterKansas CityMissouriUSA
| | - Talia Golan
- Oncology Institute, Sheba M9edical Center at Tel‐HashomerTel Aviv UniversityTel AvivIsrael
| | - Jean‐Frédéric Blanc
- Service d'Hépato‐Gastroentérologie et d'Oncologie DigestiveGroupe Hospitalier Haut‐LévêqueCHU BordeauxPessacFrance
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28
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Zhang S, Xu Q, Sun W, Zhou J, Zhou J. Immunomodulatory effects of CDK4/6 inhibitors. Biochim Biophys Acta Rev Cancer 2023; 1878:188912. [PMID: 37182667 DOI: 10.1016/j.bbcan.2023.188912] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 04/23/2023] [Accepted: 05/10/2023] [Indexed: 05/16/2023]
Abstract
The dysregulation of the cell cycle is one of the hallmarks of cancer. Cyclin-dependent kinase 4 (CDK4) and CDK6 play crucial roles in regulating cell cycle and other cellular functions. CDK4/6 inhibitors have achieved great success in treating breast cancers and are currently being tested extensively in other tumor types as well. Accumulating evidence suggests that CDK4/6 inhibitors exert antitumor effects through immunomodulation aside from cell cycle arrest. Here we outline the immunomodulatory activities of CDK4/6 inhibitors, discuss the immune mechanisms of drug resistance and explore avenues to harness their immunotherapeutic potential when combined with immune checkpoint inhibitors (ICIs) or chimeric antigen receptor (CAR) T-cell therapy to improve the clinical outcomes.
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Affiliation(s)
- Shumeng Zhang
- Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qiaomai Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wenjia Sun
- Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jianya Zhou
- Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Jianying Zhou
- Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Lawal B, Kuo YC, Wu ATH, Huang HS. Therapeutic potential of EGFR/mTOR/Nf-kb targeting small molecule for the treatment of non-small cell lung cancer. Am J Cancer Res 2023; 13:2598-2616. [PMID: 37424807 PMCID: PMC10326574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 05/28/2023] [Indexed: 07/11/2023] Open
Abstract
Despite the therapeutic advancement with chemotherapy and targeted therapy against non-small-cell lung cancer (NSCLC), most patients ultimately develop resistance to these drugs, exhibiting disease progression, metastasis, and worse prognosis. There is, therefore, a need for the development of novel multi-targeted therapies that can offer a high therapeutic index with lesser chances of drug resistance against NSCLC. In the present study, we evaluated the therapeutic potential of a novel multi-target small molecule NLOC-015A for targeted treatment of NSCLC. Our in vitro studies revealed that NLOC-015A exhibited a broad spectrum of anticancer activities against lung cancer cell line. NLOC-015A decreased the viability of H1975 and H1299 cells with respective IC50 values of 2.07±0.19 and 1.90±0.23 µm. In addition, NLOC-015A attenuated the oncogenic properties (colony formation, migratory ability, and spheroid formation) with concomitant downregulation of expression levels of epidermal growth factor receptor (EGFR)/mammalian target of rapamycin (mTOR)/AKT, nuclear factor (NF)-κB, signaling network. In addition, the stemness inhibitory effect of NLOC0-15A was accompanied by decreased expression levels of aldehyde dehydrogenase (ALDH), MYC Proto-Oncogene (C-Myc), and (sex-determining region Y)-box 2 (SOX2) in both H1975 and H1299 cell lines. Furthermore, NLOC-015A suppressed the tumor burden and increased the body weight and survival of H1975 xenograft-bearing mice. Treatment with NLOC-015A also attenuated biochemical and hematological alterations in the tumor bearing mice. Interestingly, NLOC-015A synergistically enhanced the in vitro efficacy, and therapeutic outcome of osimertinib in vivo. In addition, the toxicity of osimertinib was significantly attenuated by combination with NLOC-015A. Altogether, our findings suggested that combining osimertinib with NLOC-015 appears to be a promising way to improve osimertinib's efficacy and achieve better therapeutic results against NSCLC. We therefore suggest that NLOC-015A might represent a new candidate for treating NSCLC via acting as a multitarget inhibitor of EGFR/mTOR/NF-Κb signaling networks and efficiently compromising the oncogenic phenotype of NSCLC.
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Affiliation(s)
- Bashir Lawal
- UPMC Hillman Cancer Center, University of PittsburghPittsburgh, PA 15260, USA
- Department of Pathology, University of PittsburghPittsburgh, PA 15260, USA
| | - Yu-Cheng Kuo
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical UniversityTaipei 11031, Taiwan
- School of Post-baccalaureate Chinese Medicine, College of Chinese Medicine, China Medical UniversityTaichung 40402, Taiwan
| | - Alexander TH Wu
- The PhD Program of Translational Medicine, College of Medical Science and Technology, Taipei Medical UniversityTaipei 11031, Taiwan
- Clinical Research Center, Taipei Medical University Hospital, Taipei Medical UniversityTaipei 11031, Taiwan
- TMU Research Center of Cancer Translational Medicine, Taipei Medical UniversityTaipei 11031, Taiwan
- Graduate Institute of Medical Sciences, National Defense Medical CenterTaipei 11490, Taiwan
| | - Hsu-Shan Huang
- Graduate Institute of Medical Sciences, National Defense Medical CenterTaipei 11490, Taiwan
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia SinicaTaipei 11031, Taiwan
- Graduate Institute for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical UniversityTaipei 11031, Taiwan
- School of Pharmacy, National Defense Medical CenterTaipei 11490, Taiwan
- PhD Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical UniversityTaipei 11031, Taiwan
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30
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Cheung AHK, Hui CHL, Wong KY, Liu X, Chen B, Kang W, To KF. Out of the cycle: Impact of cell cycle aberrations on cancer metabolism and metastasis. Int J Cancer 2023; 152:1510-1525. [PMID: 36093588 DOI: 10.1002/ijc.34288] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 08/17/2022] [Accepted: 09/02/2022] [Indexed: 11/11/2022]
Abstract
The use of cell cycle inhibitors has necessitated a better understanding of the cell cycle in tumor biology to optimize the therapeutic approach. Cell cycle aberrations are common in cancers, and it is increasingly acknowledged that these aberrations exert oncogenic effects beyond the cell cycle. Multiple facets such as cancer metabolism, immunity and metastasis are also affected, all of which are beyond the effect of cell proliferation alone. This review comprehensively summarized the important recent findings and advances in these interrelated processes. In cancer metabolism, cell cycle regulators can modulate various pathways in aerobic glycolysis, glucose uptake and gluconeogenesis, mainly through transcriptional regulation and kinase activities. Amino acid metabolism is also regulated through cell cycle progression. On cancer metastasis, metabolic plasticity, immune evasion, tumor microenvironment adaptation and metastatic site colonization are intricately related to the cell cycle, with distinct regulatory mechanisms at each step of invasion and dissemination. Throughout the synthesis of current understanding, knowledge gaps and limitations in the literature are also highlighted, as are new therapeutic approaches such as combinational therapy and challenges in tackling emerging targeted therapy resistance. A greater understanding of how the cell cycle modulates diverse aspects of cancer biology can hopefully shed light on identifying new molecular targets by harnessing the vast potential of the cell cycle.
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Affiliation(s)
- Alvin Ho-Kwan Cheung
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.,Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.,State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, China
| | - Chris Ho-Lam Hui
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.,Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.,State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, China
| | - Kit Yee Wong
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.,Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.,State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, China
| | - Xiaoli Liu
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.,Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.,State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, China
| | - Bonan Chen
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.,Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.,State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, China
| | - Wei Kang
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.,Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.,State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, China
| | - Ka Fai To
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.,Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.,State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, China
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31
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Silvis MR, Silva D, Rohweder R, Schuman S, Gudipaty S, Truong A, Yap J, Affolter K, McMahon M, Kinsey C. MYC-mediated resistance to trametinib and HCQ in PDAC is overcome by CDK4/6 and lysosomal inhibition. J Exp Med 2023; 220:e20221524. [PMID: 36719686 PMCID: PMC9930170 DOI: 10.1084/jem.20221524] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 12/02/2022] [Accepted: 12/20/2022] [Indexed: 02/01/2023] Open
Abstract
Pharmacological inhibition of KRAS>RAF>MEK1/2>ERK1/2 signaling has provided no clinical benefit to patients with pancreatic ductal adenocarcinoma (PDAC). Interestingly, combined inhibition of MEK1/2 (with trametinib [T]) plus autophagy (with chloroquine [CQ] or hydroxychloroquine [HCQ]) demonstrated striking anti-tumor effects in preclinical models and in a patient (Patient 1). However, not all patients respond to the T/HCQ regimen, and Patient 1 eventually developed resistant disease. Here we report that primary or acquired resistance is associated with focal DNA copy number gains encompassing c-MYC. Furthermore, ectopic expression of c-MYC in PDAC cell lines rendered them T/HCQ resistant. Interestingly, a CDK4/6 inhibitor, palbociclib (P), also induced autophagy and overrode c-MYC-mediated T/HCQ resistance, such that P/HCQ promoted regression of T/HCQ-resistant PDAC tumors with elevated c-MYC expression. Finally, P/HCQ treatment of Patient 1 resulted in a biochemical disease response. These data suggest that elevated c-MYC expression is both a marker and a mediator of T/HCQ resistance, which may be overcome by the use of P/HCQ.
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Affiliation(s)
- Mark R. Silvis
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
| | - Dilru Silva
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
- Department of Oncological Sciences, University of Utah, Salt Lake City, UT, USA
| | - Riley Rohweder
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
| | - Sophia Schuman
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
| | | | | | - Jeffrey Yap
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
- Department of Radiology, University of Utah, Salt Lake City, UT, USA
| | - Kajsa Affolter
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
- Department of Pathology, University of Utah, Salt Lake City, UT, USA
| | - Martin McMahon
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
- Department of Oncological Sciences, University of Utah, Salt Lake City, UT, USA
- Department of Dermatology, University of Utah, Salt Lake City, UT, USA
| | - Conan Kinsey
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
- Department of Internal Medicine, Division of Oncology, University of Utah, Salt Lake City, UT, USA
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32
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Akbaş N, Akbaş EM, Süleyman Z, Çiçek B, Ağgül AG, Mokhtare B, Süleyman H. Effect of adenosine triphosphate on ribociclib-induced skin toxicity in rats. Cutan Ocul Toxicol 2023; 42:32-37. [PMID: 36656642 DOI: 10.1080/15569527.2023.2166524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
PURPOSE Ribociclib is a CDK4/6 inhibitor approved for the treatment of breast cancer; it inhibits the activity of CDK4/6 by competitively binding to adenosine 5'-triphosphate (ATP) binding sites. Although generally well-tolerated, ribociclib has been connected to a number of serious dermatologic complications. This study explored the effects of ATP on ribociclib-induced skin damage. MATERIALS AND METHODS Using a rat model, ATP 25 mg/kg was injected intraperitoneally in the ATP + Ribociclib (ATR) group (n = 6). Distilled water as solvent was applied to the healthy control (HC) group (n = 6) and ribociclib (RCB) group (n = 6). One hour after ATP and solvent administration, ribociclib (200 mg/kg) suspension prepared in distilled water was administered to the stomach by gavage (ATR and RCB groups). This was repeated once a day for 15 d. After that period, biochemical markers were studied in the skin tissues and histopathological evaluations were conducted. RESULTS In the histopathological evaluation of the RCB group, dermal necrosis, degeneration in hair follicles, and pycnosis in keratinocytes were observed. Only mild degeneration was observed in the ATR group; the HC group had a normal histological appearance. The malondialdehyde (MDA) values were significantly higher and the superoxide dismutase (SOD), catalase (CAT), and total glutathione (tGSH) levels were significantly lower in the RCB group in comparison to the HC group (p < .001). ATP reduced the ribociclib-induced increases in the MDA values and decreased the SOD, CAT, and tGSH levels in the ATR group (p < .001). CONCLUSION ATP may be useful in the treatment of ribociclib-induced skin damage.
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Affiliation(s)
- Nergis Akbaş
- Department of Medical Biochemistry, School of Medicine, Erzincan Binali Yıldırım University, Erzincan, Turkey
| | - Emin Murat Akbaş
- Department of Internal Medicine, School of Medicine, Erzincan Binali Yıldırım University, Erzincan, Turkey
| | - Zeynep Süleyman
- Department of Pharmacology, School of Medicine, Erzincan Binali Yıldırım University, Erzincan, Turkey
| | - Betül Çiçek
- Department of Phisiology, School of Medicine, Erzincan Binali Yıldırım University, Erzincan, Turkey
| | - Ahmet Gökhan Ağgül
- Department of Biochemistry, School of Pharmacy, Ağrı İbrahim Çeçen University, Ağrı, Turkey
| | - Behzad Mokhtare
- Department of Pathology, Faculty of Veterinary Medicine, Atatürk University, Erzurum, Turkey
| | - Halis Süleyman
- Department of Pharmacology, School of Medicine, Erzincan Binali Yıldırım University, Erzincan, Turkey
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Tau S, Miller TW. The role of cancer cell bioenergetics in dormancy and drug resistance. Cancer Metastasis Rev 2023; 42:87-98. [PMID: 36696004 PMCID: PMC10233409 DOI: 10.1007/s10555-023-10081-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 01/11/2023] [Indexed: 01/26/2023]
Abstract
While anti-cancer drug treatments are often effective for the clinical management of cancer, these treatments frequently leave behind drug-tolerant persister cancer cells that can ultimately give rise to recurrent disease. Such persistent cancer cells can lie dormant for extended periods of time, going undetected by conventional clinical means. Understanding the mechanisms that such dormant cancer cells use to survive, and the mechanisms that drive emergence from dormancy, is critical to the development of improved therapeutic strategies to prevent and manage disease recurrence. Cancer cells often exhibit metabolic alterations compared to their non-transformed counterparts. An emerging body of evidence supports the notion that dormant cancer cells also have unique metabolic adaptations that may offer therapeutically targetable vulnerabilities. Herein, we review mechanisms through which cancer cells metabolically adapt to persist during drug treatments and develop drug resistance. We also highlight emerging therapeutic strategies to target dormant cancer cells via their metabolic features.
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Affiliation(s)
- Steven Tau
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Dartmouth Cancer Center, Lebanon, NH, USA
| | - Todd W Miller
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Dartmouth Cancer Center, Lebanon, NH, USA.
- Dartmouth-Hitchcock Medical Center, One Medical Center Drive, HB-7936, Lebanon, NH 03756, USA.
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34
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Velez BC, Petrella CP, DiSalvo KH, Cheng K, Kravtsov R, Krasniqi D, Krucher NA. Combined inhibition of ACLY and CDK4/6 reduces cancer cell growth and invasion. Oncol Rep 2023; 49:32. [PMID: 36562384 PMCID: PMC9827262 DOI: 10.3892/or.2022.8469] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 11/23/2022] [Indexed: 12/24/2022] Open
Abstract
The use of small molecule kinase inhibitors, which target specific enzymes that are overactive in cancer cells, has revolutionized cancer patient treatment. To treat some types of breast cancer, CDK4/6 inhibitors, such as palbociclib, have been developed that target the phosphorylation of the retinoblastoma tumor suppressor gene. Acquired resistance to CDK4/6 inhibitors may be due to activation of the AKT pro‑survival signaling pathway that stimulates several processes, such as growth, metastasis and changes in metabolism that support rapid cell proliferation. The aim of the present study was to investigate whether targeting ATP citrate lyase (ACLY), a downstream target of AKT, may combine with CDK4/6 inhibition to inhibit tumorigenesis. The present study determined that ACLY is activated in breast and pancreatic cancer cells in response to palbociclib treatment and AKT mediates this effect. Inhibition of ACLY using bempedoic acid used in combination with palbociclib reduced cell viability in a panel of breast and pancreatic cancer cell lines. This effect was also observed using breast cancer cells grown in 3D cell culture. Mechanistically, palbociclib inhibited cell proliferation, whereas bempedoic acid stimulated apoptosis. Finally, using Transwell invasion assays and immunoblotting, the present study demonstrated that ACLY inhibition blocked cell invasion, when used alone or in combination with palbociclib. These data may yield useful information that could guide the development of future therapies aimed at the reduction of acquired resistance observed clinically.
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Affiliation(s)
| | | | | | - Keyi Cheng
- Department of Biology, Pace University, Pleasantville, NY 10570, USA
| | - Rebecca Kravtsov
- Department of Biology, Pace University, Pleasantville, NY 10570, USA
| | - Dorina Krasniqi
- Department of Biology, Pace University, Pleasantville, NY 10570, USA
| | - Nancy Ann Krucher
- Department of Biology, Pace University, Pleasantville, NY 10570, USA
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35
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Goodwin CM, Waters AM, Klomp JE, Javaid S, Bryant KL, Stalnecker CA, Drizyte-Miller K, Papke B, Yang R, Amparo AM, Ozkan-Dagliyan I, Baldelli E, Calvert V, Pierobon M, Sorrentino JA, Beelen AP, Bublitz N, Lüthen M, Wood KC, Petricoin EF, Sers C, McRee AJ, Cox AD, Der CJ. Combination Therapies with CDK4/6 Inhibitors to Treat KRAS-Mutant Pancreatic Cancer. Cancer Res 2023; 83:141-157. [PMID: 36346366 PMCID: PMC9812941 DOI: 10.1158/0008-5472.can-22-0391] [Citation(s) in RCA: 73] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 08/08/2022] [Accepted: 10/28/2022] [Indexed: 11/09/2022]
Abstract
Mutational loss of CDKN2A (encoding p16INK4A) tumor-suppressor function is a key genetic step that complements activation of KRAS in promoting the development and malignant growth of pancreatic ductal adenocarcinoma (PDAC). However, pharmacologic restoration of p16INK4A function with inhibitors of CDK4 and CDK6 (CDK4/6) has shown limited clinical efficacy in PDAC. Here, we found that concurrent treatment with both a CDK4/6 inhibitor (CDK4/6i) and an ERK-MAPK inhibitor (ERKi) synergistically suppresses the growth of PDAC cell lines and organoids by cooperatively blocking CDK4/6i-induced compensatory upregulation of ERK, PI3K, antiapoptotic signaling, and MYC expression. On the basis of these findings, a Phase I clinical trial was initiated to evaluate the ERKi ulixertinib in combination with the CDK4/6i palbociclib in patients with advanced PDAC (NCT03454035). As inhibition of other proteins might also counter CDK4/6i-mediated signaling changes to increase cellular CDK4/6i sensitivity, a CRISPR-Cas9 loss-of-function screen was conducted that revealed a spectrum of functionally diverse genes whose loss enhanced CDK4/6i growth inhibitory activity. These genes were enriched around diverse signaling nodes, including cell-cycle regulatory proteins centered on CDK2 activation, PI3K-AKT-mTOR signaling, SRC family kinases, HDAC proteins, autophagy-activating pathways, chromosome regulation and maintenance, and DNA damage and repair pathways. Novel therapeutic combinations were validated using siRNA and small-molecule inhibitor-based approaches. In addition, genes whose loss imparts a survival advantage were identified (e.g., RB1, PTEN, FBXW7), suggesting possible resistance mechanisms to CDK4/6 inhibition. In summary, this study has identified novel combinations with CDK4/6i that may have clinical benefit to patients with PDAC. SIGNIFICANCE CRISPR-Cas9 screening and protein activity mapping reveal combinations that increase potency of CDK4/6 inhibitors and overcome drug-induced compensations in pancreatic cancer.
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Affiliation(s)
- Craig M. Goodwin
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Andrew M. Waters
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Jennifer E. Klomp
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Sehrish Javaid
- Program in Oral and Craniofacial Biomedicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Kirsten L. Bryant
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
- Department of Pharmacology, George Mason University, Fairfax, Virginia
| | - Clint A. Stalnecker
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Kristina Drizyte-Miller
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Bjoern Papke
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
- Charité Universitätsmedizin Berlin, Institute of Pathology, Laboratory of Molecular Tumor Pathology and Systems Biology, 10117 Berlin, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Berlin Institute of Health (BIH), Anna-Louise-Karsch-Str. 2, 10178 Berlin, Germany
| | - Runying Yang
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Amber M. Amparo
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | | | - Elisa Baldelli
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Fairfax, Virginia
| | - Valerie Calvert
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Fairfax, Virginia
| | - Mariaelena Pierobon
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Fairfax, Virginia
| | | | | | - Natalie Bublitz
- Charité Universitätsmedizin Berlin, Institute of Pathology, Laboratory of Molecular Tumor Pathology and Systems Biology, 10117 Berlin, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Berlin Institute of Health (BIH), Anna-Louise-Karsch-Str. 2, 10178 Berlin, Germany
| | - Mareen Lüthen
- Charité Universitätsmedizin Berlin, Institute of Pathology, Laboratory of Molecular Tumor Pathology and Systems Biology, 10117 Berlin, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Berlin Institute of Health (BIH), Anna-Louise-Karsch-Str. 2, 10178 Berlin, Germany
| | - Kris C. Wood
- Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina
| | - Emanuel F. Petricoin
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Fairfax, Virginia
| | - Christine Sers
- Charité Universitätsmedizin Berlin, Institute of Pathology, Laboratory of Molecular Tumor Pathology and Systems Biology, 10117 Berlin, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Berlin Institute of Health (BIH), Anna-Louise-Karsch-Str. 2, 10178 Berlin, Germany
| | - Autumn J. McRee
- Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Adrienne D. Cox
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
- Department of Pharmacology, George Mason University, Fairfax, Virginia
- Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Channing J. Der
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
- Department of Pharmacology, George Mason University, Fairfax, Virginia
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36
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Kreuger IZM, Slieker RC, van Groningen T, van Doorn R. Therapeutic Strategies for Targeting CDKN2A Loss in Melanoma. J Invest Dermatol 2023; 143:18-25.e1. [PMID: 36123181 DOI: 10.1016/j.jid.2022.07.016] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 07/25/2022] [Accepted: 07/26/2022] [Indexed: 11/30/2022]
Abstract
Loss of the tumor suppressor gene CDKN2A, encoding p16 and p14, is a frequent event driving melanoma progression. Therefore, therapeutic strategies aimed at CDKN2A loss hold great potential to improve melanoma treatment. Pharmacological inhibition of the p16 targets CDK4/6 is a prime example of such a strategy. Other approaches exploit cell cycle deregulation, target metabolic rewiring, epigenetically restore expression, act on dependencies resulting from co-deleted genes, or are directed at the effects of CDKN2A loss on immune responses. This review explores these therapeutic strategies targeting CDKN2A loss, which potentially open up new avenues for precision medicine in melanoma.
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Affiliation(s)
- Inger Z M Kreuger
- Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands; Leiden Center for Computational Oncology, Leiden University Medical Center, Leiden, The Netherlands
| | - Roderick C Slieker
- Leiden Center for Computational Oncology, Leiden University Medical Center, Leiden, The Netherlands; Department of Cell & Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands
| | - Tim van Groningen
- Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands; Leiden Center for Computational Oncology, Leiden University Medical Center, Leiden, The Netherlands
| | - Remco van Doorn
- Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands; Leiden Center for Computational Oncology, Leiden University Medical Center, Leiden, The Netherlands.
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37
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Chibaya L, Snyder J, Ruscetti M. Senescence and the tumor-immune landscape: Implications for cancer immunotherapy. Semin Cancer Biol 2022; 86:827-845. [PMID: 35143990 PMCID: PMC9357237 DOI: 10.1016/j.semcancer.2022.02.005] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 02/03/2022] [Indexed: 01/27/2023]
Abstract
Cancer therapies, including conventional chemotherapy, radiation, and molecularly targeted agents, can lead to tumor eradication through a variety of mechanisms. In addition to their effects on tumor cell growth and survival, these regimens can also influence the surrounding tumor-immune microenvironment in ways that ultimately impact therapy responses. A unique biological outcome of cancer therapy is induction of cellular senescence. Senescence is a damage-induced stress program that leads to both the durable arrest of tumor cells and remodeling the tumor-immune microenvironment through activation of a collection pleiotropic cytokines, chemokines, growth factors, and proteinases known as the senescence-associated secretory phenotype (SASP). Depending on the cancer context and the mechanism of action of the therapy, the SASP produced following therapy-induced senescence (TIS) can promote anti-tumor immunity that enhances therapeutic efficacy, or alternatively chronic inflammation that leads to therapy failure and tumor relapse. Thus, a deeper understanding of the mechanisms regulating the SASP and components necessary for robust anti-tumor immune surveillance in different cancer and therapy contexts are key to harnessing senescence for tumor control. Here we draw a roadmap to modulate TIS and its immune-stimulating features for cancer immunotherapy.
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Affiliation(s)
- Loretah Chibaya
- Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Jarin Snyder
- Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Marcus Ruscetti
- Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA; Immunology and Microbiology Program, University of Massachusetts Chan Medical School, Worcester, MA, USA; Cancer Center, University of Massachusetts Chan Medical School, Worcester, MA, USA.
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38
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Pedrosa L, Foguet C, Oliveres H, Archilla I, de Herreros MG, Rodríguez A, Postigo A, Benítez-Ribas D, Camps J, Cuatrecasas M, Castells A, Prat A, Thomson TM, Maurel J, Cascante M. A novel gene signature unveils three distinct immune-metabolic rewiring patterns conserved across diverse tumor types and associated with outcomes. Front Immunol 2022; 13:926304. [PMID: 36119118 PMCID: PMC9479210 DOI: 10.3389/fimmu.2022.926304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 07/27/2022] [Indexed: 11/23/2022] Open
Abstract
Existing immune signatures and tumor mutational burden have only modest predictive capacity for the efficacy of immune check point inhibitors. In this study, we developed an immune-metabolic signature suitable for personalized ICI therapies. A classifier using an immune-metabolic signature (IMMETCOLS) was developed on a training set of 77 metastatic colorectal cancer (mCRC) samples and validated on 4,200 tumors from the TCGA database belonging to 11 types. Here, we reveal that the IMMETCOLS signature classifies tumors into three distinct immune-metabolic clusters. Cluster 1 displays markers of enhanced glycolisis, hexosamine byosinthesis and epithelial-to-mesenchymal transition. On multivariate analysis, cluster 1 tumors were enriched in pro-immune signature but not in immunophenoscore and were associated with the poorest median survival. Its predicted tumor metabolic features suggest an acidic-lactate-rich tumor microenvironment (TME) geared to an immunosuppressive setting, enriched in fibroblasts. Cluster 2 displays features of gluconeogenesis ability, which is needed for glucose-independent survival and preferential use of alternative carbon sources, including glutamine and lipid uptake/β-oxidation. Its metabolic features suggest a hypoxic and hypoglycemic TME, associated with poor tumor-associated antigen presentation. Finally, cluster 3 is highly glycolytic but also has a solid mitochondrial function, with concomitant upregulation of glutamine and essential amino acid transporters and the pentose phosphate pathway leading to glucose exhaustion in the TME and immunosuppression. Together, these findings suggest that the IMMETCOLS signature provides a classifier of tumors from diverse origins, yielding three clusters with distinct immune-metabolic profiles, representing a new predictive tool for patient selection for specific immune-metabolic therapeutic approaches.
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Affiliation(s)
- Leire Pedrosa
- Medical Oncology Department, Hospital Clínic of Barcelona, Translational Genomics and Targeted Therapeutics in Solid Tumors Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Carles Foguet
- Department of Biochemistry and Molecular Biomedicine and Institute of Biomedicine (IBUB), Universitat de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
| | - Helena Oliveres
- Medical Oncology Department, Hospital Clínic of Barcelona, Translational Genomics and Targeted Therapeutics in Solid Tumors Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Iván Archilla
- Pathology Department, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Marta García de Herreros
- Medical Oncology Department, Hospital Clínic of Barcelona, Translational Genomics and Targeted Therapeutics in Solid Tumors Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Adela Rodríguez
- Medical Oncology Department, Hospital Clínic of Barcelona, Translational Genomics and Targeted Therapeutics in Solid Tumors Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Antonio Postigo
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Group of Transcriptional Regulation of Gene Expression, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Institución Catalana de Investigación y Estudios Avanzados (ICREA) and Department of Biomedicine, Universitat de Barcelona, Barcelona, Spain
| | | | - Jordi Camps
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Gastrointestinal Oncology Department, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Miriam Cuatrecasas
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Pathology Department, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Antoni Castells
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Gastrointestinal Oncology Department, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Aleix Prat
- Medical Oncology Department, Hospital Clínic of Barcelona, Translational Genomics and Targeted Therapeutics in Solid Tumors Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Timothy M. Thomson
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Department of Cell Biology, Molecular Biology Institute, National Research Council (IBMB-CSIC), Barcelona, Spain
- Universidad Peruana Cayetano Heredia, Lima, Peru
- *Correspondence: Timothy M. Thomson, ; Joan Maurel, ; Marta Cascante,
| | - Joan Maurel
- Medical Oncology Department, Hospital Clínic of Barcelona, Translational Genomics and Targeted Therapeutics in Solid Tumors Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Gastrointestinal Oncology Department, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- *Correspondence: Timothy M. Thomson, ; Joan Maurel, ; Marta Cascante,
| | - Marta Cascante
- Department of Biochemistry and Molecular Biomedicine and Institute of Biomedicine (IBUB), Universitat de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- *Correspondence: Timothy M. Thomson, ; Joan Maurel, ; Marta Cascante,
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39
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Rudloff U. Emerging kinase inhibitors for the treatment of pancreatic ductal adenocarcinoma. Expert Opin Emerg Drugs 2022; 27:345-368. [PMID: 36250721 PMCID: PMC9793333 DOI: 10.1080/14728214.2022.2134346] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 08/22/2022] [Accepted: 10/06/2022] [Indexed: 01/09/2023]
Abstract
INTRODUCTION Pancreatic cancer is one of the deadliest solid organ cancers. In the absence of specific warning symptoms pancreatic cancer is diagnosed notoriously late. Current systemic chemotherapy regimens extend survival by a mere few months. With the advances in genetic, proteomic, and immunological profiling there is strong rationale to test kinase inhibitors to improve outcome. AREAS COVERED This review article provides a comprehensive summary of approved treatments and past, present, and future developments of kinase inhibitors in pancreatic cancer. Emerging roles of protein kinase inhibitors are discussed in the context of the unique stroma, the lack of high-prevalence therapeutic targets and rapid emergence of acquired resistance, novel immuno-oncology kinase targets, and recent medicinal chemistry advances. EXPERT OPINION Due to the to-date frequent failure of protein kinase inhibitors indiscriminately administered to unselected pancreatic cancer patients, there is a shift toward the development of these agents in molecularly defined subgroups which are more likely to respond. The development of accurate biomarkers to select patients who are the best candidates based on a detailed understanding of mechanism of action, pro-survival roles, and mediation of resistance of targeted kinases will be critical for the future development of protein kinase inhibitors in this disease.
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Affiliation(s)
- Udo Rudloff
- Rare Tumor Initiative, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
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40
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Lin CY, Yu CJ, Liu CY, Chao TC, Huang CC, Tseng LM, Lai JI. CDK4/6 inhibitors downregulate the ubiquitin-conjugating enzymes UBE2C/S/T involved in the ubiquitin-proteasome pathway in ER + breast cancer. CLINICAL & TRANSLATIONAL ONCOLOGY : OFFICIAL PUBLICATION OF THE FEDERATION OF SPANISH ONCOLOGY SOCIETIES AND OF THE NATIONAL CANCER INSTITUTE OF MEXICO 2022; 24:2120-2135. [PMID: 35917055 DOI: 10.1007/s12094-022-02881-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 06/20/2022] [Indexed: 10/16/2022]
Abstract
Despite significant improvement in therapeutic development in the past decades, breast cancer remains a formidable cause of death for women worldwide. The hormone positive subtype (HR( +)) (also known as luminal type) is the most prevalent category of breast cancer, comprising ~ 70% of patients. The clinical success of the three CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib has revolutionized the treatment of choice for metastatic HR( +) breast cancer. Accumulating evidence demonstrate that the properties of CDK4/6 inhibitors extend beyond inhibition of the cell cycle, including modulation of immune function, sensitizing PI3K inhibitors, metabolism reprogramming, kinome rewiring, modulation of the proteasome, and many others. The ubiquitin-proteasome pathway (UPP) is a crucial cellular proteolytic system that maintains the homeostasis and turnover of proteins. By transcriptional profiling of the HR( +) breast cancer cell lines MCF7 and T47D treated with Palbociclib, we have uncovered a novel mechanism that demonstrates that the CDK4/6 inhibitors suppress the expression of three ubiquitin-conjugating enzymes UBE2C, UBE2S, UBE2T. Further validation in the HR( +) cell lines show that Palbociclib and ribociclib decrease UBE2C at both the mRNA and protein level, but this phenomenon was not shared with abemaciclib. These three E2 enzymes modulate several E3 ubiquitin ligases, including the APC/C complex which plays a role in G1/S progression. We further demonstrate that the UBE2C/UBE2T expression levels are associated with breast cancer survival, and HR( +) breast cancer cells demonstrate dependence on the UBE2C. Our study suggests a novel link between CDK4/6 inhibitor and UPP pathway, adding to the potential mechanisms of their clinical efficacy in cancer.
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Affiliation(s)
- Chih-Yi Lin
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chung-Jen Yu
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chun-Yu Liu
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.,Division of Transfusion Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,Comprehensive Breast Health Center, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ta-Chung Chao
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.,Comprehensive Breast Health Center, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chi-Cheng Huang
- Comprehensive Breast Health Center, Taipei Veterans General Hospital, Taipei, Taiwan.,Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ling-Ming Tseng
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Comprehensive Breast Health Center, Taipei Veterans General Hospital, Taipei, Taiwan.,Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Jiun-I Lai
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan. .,Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan. .,Comprehensive Breast Health Center, Taipei Veterans General Hospital, Taipei, Taiwan. .,Center of Immuno-Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
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41
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Tian Q, Wang G, Ma X, Shen Q, Ding M, Yang X, Luo X, Li R, Wang Z, Wang X, Fu Z, Yang Q, Tang J, Wang G. Riboflavin integrates cellular energetics and cell cycle to regulate maize seed development. PLANT BIOTECHNOLOGY JOURNAL 2022; 20:1487-1501. [PMID: 35426230 PMCID: PMC9342611 DOI: 10.1111/pbi.13826] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Accepted: 04/10/2022] [Indexed: 05/23/2023]
Abstract
Riboflavin is the precursor of essential cofactors for diverse metabolic processes. Unlike animals, plants can de novo produce riboflavin through an ancestrally conserved pathway, like bacteria and fungi. However, the mechanism by which riboflavin regulates seed development is poorly understood. Here, we report a novel maize (Zea mays L.) opaque mutant o18, which displays an increase in lysine accumulation, but impaired endosperm filling and embryo development. O18 encodes a rate-limiting bifunctional enzyme ZmRIBA1, targeted to plastid where to initiate riboflavin biosynthesis. Loss of function of O18 specifically disrupts respiratory complexes I and II, but also decreases SDH1 flavinylation, and in turn shifts the mitochondrial tricarboxylic acid (TCA) cycle to glycolysis. The deprivation of cellular energy leads to cell-cycle arrest at G1 and S phases in both mitosis and endoreduplication during endosperm development. The unexpected up-regulation of cell-cycle genes in o18 correlates with the increase of H3K4me3 levels, revealing a possible H3K4me-mediated epigenetic back-up mechanism for cell-cycle progression under unfavourable circumstances. Overexpression of O18 increases riboflavin production and confers osmotic tolerance. Altogether, our results substantiate a key role of riboflavin in coordinating cellular energy and cell cycle to modulate maize endosperm development.
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Affiliation(s)
- Qiuzhen Tian
- National Key Laboratory of Wheat and Maize Crops ScienceCIMMYT‐Henan Joint Center for Wheat and Maize ImprovementCollaborative Innovation Center of Henan Grain CropsCollege of AgronomyHenan Agricultural UniversityZhengzhouChina
| | - Gang Wang
- School of Agriculture and BiologyShanghai Jiao Tong UniversityShanghaiChina
| | - Xuexia Ma
- Shanghai Key Laboratory of Bio‐Energy CropsSchool of Life SciencesShanghai UniversityShanghaiChina
| | - Qingwen Shen
- National Key Laboratory of Wheat and Maize Crops ScienceCIMMYT‐Henan Joint Center for Wheat and Maize ImprovementCollaborative Innovation Center of Henan Grain CropsCollege of AgronomyHenan Agricultural UniversityZhengzhouChina
| | - Mengli Ding
- National Key Laboratory of Wheat and Maize Crops ScienceCIMMYT‐Henan Joint Center for Wheat and Maize ImprovementCollaborative Innovation Center of Henan Grain CropsCollege of AgronomyHenan Agricultural UniversityZhengzhouChina
| | - Xueyi Yang
- National Key Laboratory of Wheat and Maize Crops ScienceCIMMYT‐Henan Joint Center for Wheat and Maize ImprovementCollaborative Innovation Center of Henan Grain CropsCollege of AgronomyHenan Agricultural UniversityZhengzhouChina
| | - Xiaoli Luo
- National Key Laboratory of Wheat and Maize Crops ScienceCIMMYT‐Henan Joint Center for Wheat and Maize ImprovementCollaborative Innovation Center of Henan Grain CropsCollege of AgronomyHenan Agricultural UniversityZhengzhouChina
| | - Rongrong Li
- National Key Laboratory of Wheat and Maize Crops ScienceCIMMYT‐Henan Joint Center for Wheat and Maize ImprovementCollaborative Innovation Center of Henan Grain CropsCollege of AgronomyHenan Agricultural UniversityZhengzhouChina
| | - Zhenghui Wang
- National Key Laboratory of Wheat and Maize Crops ScienceCIMMYT‐Henan Joint Center for Wheat and Maize ImprovementCollaborative Innovation Center of Henan Grain CropsCollege of AgronomyHenan Agricultural UniversityZhengzhouChina
| | - Xiangyang Wang
- National Key Laboratory of Wheat and Maize Crops ScienceCIMMYT‐Henan Joint Center for Wheat and Maize ImprovementCollaborative Innovation Center of Henan Grain CropsCollege of AgronomyHenan Agricultural UniversityZhengzhouChina
| | - Zhiyuan Fu
- National Key Laboratory of Wheat and Maize Crops ScienceCIMMYT‐Henan Joint Center for Wheat and Maize ImprovementCollaborative Innovation Center of Henan Grain CropsCollege of AgronomyHenan Agricultural UniversityZhengzhouChina
| | - Qinghua Yang
- National Key Laboratory of Wheat and Maize Crops ScienceCIMMYT‐Henan Joint Center for Wheat and Maize ImprovementCollaborative Innovation Center of Henan Grain CropsCollege of AgronomyHenan Agricultural UniversityZhengzhouChina
| | - Jihua Tang
- National Key Laboratory of Wheat and Maize Crops ScienceCIMMYT‐Henan Joint Center for Wheat and Maize ImprovementCollaborative Innovation Center of Henan Grain CropsCollege of AgronomyHenan Agricultural UniversityZhengzhouChina
- The Shennong LaboratoryZhengzhouChina
| | - Guifeng Wang
- National Key Laboratory of Wheat and Maize Crops ScienceCIMMYT‐Henan Joint Center for Wheat and Maize ImprovementCollaborative Innovation Center of Henan Grain CropsCollege of AgronomyHenan Agricultural UniversityZhengzhouChina
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42
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Kumarasamy V, Nambiar R, Wang J, Rosenheck H, Witkiewicz AK, Knudsen ES. RB loss determines selective resistance and novel vulnerabilities in ER-positive breast cancer models. Oncogene 2022; 41:3524-3538. [PMID: 35676324 PMCID: PMC10680093 DOI: 10.1038/s41388-022-02362-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 05/11/2022] [Accepted: 05/24/2022] [Indexed: 11/09/2022]
Abstract
The management of metastatic estrogen receptor (ER) positive HER2 negative breast cancer (ER+) has improved; however, therapeutic resistance and disease progression emerges in majority of cases. Using unbiased approaches, as expected PI3K and MTOR inhibitors emerge as potent inhibitors to delay proliferation of ER+ models harboring PIK3CA mutations. However, the cytostatic efficacy of these drugs is hindered due to marginal impact on the expression of cyclin D1. Different combination approaches involving the inhibition of ER pathway or cell cycle result in durable growth arrest via RB activation and subsequent inhibition of CDK2 activity. However, cell cycle alterations due to RB loss or ectopic CDK4/cyclin D1 activation yields resistance to these cytostatic combination treatments. To define means to counter resistance to targeted therapies imparted with RB loss; complementary drug screens were performed with RB-deleted isogenic cell lines. In this setting, RB loss renders ER+ breast cancer models more vulnerable to drugs that target DNA replication and mitosis. Pairwise combinations using these classes of drugs defines greater selectivity for RB deficiency. The combination of AURK and WEE1 inhibitors, yields synergistic cell death selectively in RB-deleted ER+ breast cancer cells via apoptosis and yields profound disease control in vivo. Through unbiased efforts the XIAP/CIAP inhibitor birinapant was identified as a novel RB-selective agent. Birinapant further enhances the cytotoxic effect of chemotherapies and targeted therapies used in the treatment of ER+ breast cancer models selectively in the RB-deficient setting. Using organoid culture and xenograft models, we demonstrate the highly selective use of birinapant based combinations for the treatment of RB-deficient tumors. Together, these data illustrate the critical role of RB-pathway in response to many agents used to treat ER+ breast cancer, whilst informing new therapeutic approaches that could be deployed against resistant disease.
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Affiliation(s)
- Vishnu Kumarasamy
- Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Ram Nambiar
- Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Jianxin Wang
- Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Hanna Rosenheck
- Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Agnieszka K Witkiewicz
- Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
| | - Erik S Knudsen
- Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
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43
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Abstract
Cyclin-dependent kinase 4 (CDK4) and CDK6 are critical mediators of cellular transition into S phase and are important for the initiation, growth and survival of many cancer types. Pharmacological inhibitors of CDK4/6 have rapidly become a new standard of care for patients with advanced hormone receptor-positive breast cancer. As expected, CDK4/6 inhibitors arrest sensitive tumour cells in the G1 phase of the cell cycle. However, the effects of CDK4/6 inhibition are far more wide-reaching. New insights into their mechanisms of action have triggered identification of new therapeutic opportunities, including the development of novel combination regimens, expanded application to a broader range of cancers and use as supportive care to ameliorate the toxic effects of other therapies. Exploring these new opportunities in the clinic is an urgent priority, which in many cases has not been adequately addressed. Here, we provide a framework for conceptualizing the activity of CDK4/6 inhibitors in cancer and explain how this framework might shape the future clinical development of these agents. We also discuss the biological underpinnings of CDK4/6 inhibitor resistance, an increasingly common challenge in clinical oncology.
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Affiliation(s)
- Shom Goel
- Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.
| | - Johann S Bergholz
- Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Jean J Zhao
- Dana-Farber Cancer Institute, Boston, MA, USA.
- Harvard Medical School, Boston, MA, USA.
- Broad Institute of Harvard and MIT, Cambridge, MA, USA.
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44
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Sun R, Wang X, Zhang L, Gu Y, Yang S, Wang L, Wang X. CDK6 Immunophenotype Implicates Potential Therapeutic Application of CDK4/6 Inhibitors in Urothelial Carcinoma. Front Oncol 2022; 12:819003. [PMID: 35463324 PMCID: PMC9024172 DOI: 10.3389/fonc.2022.819003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Accepted: 01/26/2022] [Indexed: 11/13/2022] Open
Abstract
Background Infiltrating bladder urothelial carcinoma is the most common bladder malignancy with limited therapeutic options and poor prognosis. Identifying new therapeutic targets or strategies has important clinical significance. The data from public sources indicate poor prognosis in urothelial carcinoma cases with high CDK6 mRNA levels. Furthermore, studies have shown that CDK6 expression is elevated in urothelial carcinoma tissue compared to the surrounding urothelium, thus presenting a case for performing CDK4/6 inhibitor targeted research in urothelial carcinoma. However, a phase II trial showed that CDK4/6 inhibitors are not effective for advanced urothelial carcinoma, suggesting that case screening is important for targeted therapy. Objective Immunohistochemistry (IHC) is simple and easy to perform and can be used to screen urothelial carcinoma cases with high CDK6 expression in clinical practice. The aim of this study was to determine the CDK6 expression threshold for positive cases. Methods We evaluated the correlation between the H-score of CDK6 protein expression and survival or CDK6 mRNA level using RNA sequencing. The effects of different CDK4/6 inhibitors were tested on bladder carcinoma cell lines with different CDK6 expression levels. Results The H-score, which predicts poor prognosis and reflects a high CDK6 mRNA level, was determined as the selection criterion for positive cases. Furthermore, we found that urothelial carcinoma cell lines with higher CDK6 expression levels displayed greater sensitivity to CDK4/6 inhibitors than cells with lower expression levels. Conclusions IHC staining for CDK6 protein in urothelial carcinoma is proposed as a promising screening platform for CDK4/6 inhibitor targeted therapy.
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Affiliation(s)
- Ran Sun
- Center for Reproductive Medicine, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Xuemei Wang
- Department of Pathology, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Leichao Zhang
- Department of Pathology, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Yu Gu
- Department of Pathology, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Shaojuan Yang
- Department of Pathology, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Liping Wang
- Department of Pathology, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Xueju Wang
- Department of Pathology, China-Japan Union Hospital, Jilin University, Changchun, China
- *Correspondence: Xueju Wang,
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45
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Qi J, Ouyang Z. Targeting CDK4/6 for Anticancer Therapy. Biomedicines 2022; 10:685. [PMID: 35327487 PMCID: PMC8945444 DOI: 10.3390/biomedicines10030685] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/10/2022] [Accepted: 03/14/2022] [Indexed: 12/26/2022] Open
Abstract
Cyclin-dependent kinase 4/6 (CDK4/6) are key regulators of the cell cycle and are deemed as critical therapeutic targets of multiple cancers. Various approaches have been applied to silence CDK4/6 at different levels, i.e., CRISPR to knock out at the DNA level, siRNA to inhibit translation, and drugs that target the protein of interest. Here we summarize the current status in this field, highlighting the mechanisms of small molecular inhibitors treatment and drug resistance. We describe approaches to combat drug resistance, including combination therapy and PROTACs drugs that degrade the kinases. Finally, critical issues and perspectives in the field are outlined.
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Affiliation(s)
- Jiating Qi
- The Second Clinical College, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;
| | - Zhuqing Ouyang
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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46
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Cetin B, Wabl CA, Gumusay O. CDK4/6 inhibitors: mechanisms of resistance and potential biomarkers of responsiveness in breast cancer. Future Oncol 2022; 18:1143-1157. [PMID: 35137602 DOI: 10.2217/fon-2021-0842] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Hormone receptor (HR)-positive, HER2-negative tumors represent the most common form of metastatic breast cancer (MBC), and endocrine therapy has been the mainstay treatment for several decades. Recently, a novel drug class called CDK4/6 inhibitors in combination with endocrine therapy have remarkably improved the outcome of patients with HR-positive, HER2-negative MBC by targeting the cell cycle machinery and overcoming aspects of endocrine resistance. Several potential cell-cycle-specific and nonspecific mechanisms of resistance to CDK4/6 inhibitors have been reported in recent studies. This review discusses potential resistance mechanisms to CDK4/6 inhibitors, the use of biomarkers to guide treatment for HR-positive, HER2-negative MBC and possible approaches to overcome resistance to CDK4/6 inhibitors.
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Affiliation(s)
- Bulent Cetin
- Department of Internal Medicine, Division of Medical Oncology, Suleyman Demirel University Faculty of Medicine, Isparta, 32260, Turkey
| | - Chiara A Wabl
- University of California, San Francisco School of Medicine, San Francisco, CA 94143, USA
| | - Ozge Gumusay
- University of California Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94143, USA
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47
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Chang M, Huhn S, Nelson L, Betenbaugh M, Du Z. Significant impact of mTORC1 and ATF4 pathways in CHO cell recombinant protein production induced by CDK4/6 inhibitor. Biotechnol Bioeng 2022; 119:1189-1206. [PMID: 35112712 DOI: 10.1002/bit.28050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 01/03/2022] [Accepted: 01/24/2022] [Indexed: 11/11/2022]
Abstract
The CDK4/6 inhibitor has been shown to increase recombinant protein productivity in Chinese hamster ovary cells (CHO). Therefore, we investigated the mechanism that couples cell cycle inhibitor (CCI) treatment with protein productivity utilizing proteomics and phosphoproteomics. We identified mTORC1 as a critical early signaling event that preceded boosted productivity. Following CCI treatment, mTOR exhibited a transient increase in phosphorylation at a novel site that is also conserved in human and mouse. Upstream of mTORC1, increased phosphorylation of AKT1S1 and decreased phosphorylation of RB1 may provide molecular links between CDK4/6 inhibition and mTORC1. Downstream, increased EIF4EBP phosphorylation was observed, which can mediate cap-dependent translation. In addition, the collective effect of increased phosphorylation of RPS6, increased phosphorylation of regulators of RNA polymerase I, and increased protein expression in tRNA-aminoacylation pathway may contribute to enhancing the translational apparatus for increased productivity. In concert, an elevated stress response via GCN2/EIF2AK4-ATF4 axis persisted over the treatment course, which may link mTOR to downstream responses including the unfolded protein response (UPR) and autophagy to enhance proper protein folding and secretion. Together, this comprehensive proteomics and phosphoproteomics characterization of CCI treated CHO cells offers insights into understanding multiple aspects of signaling events resulting from CDK4/CDK6 inhibition. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Meiping Chang
- Process Cell Sciences, Biologics Process R&D, Merck & Co., Inc., Kenilworth, NJ, USA
| | - Steven Huhn
- Process Cell Sciences, Biologics Process R&D, Merck & Co., Inc., Kenilworth, NJ, USA
| | - Luke Nelson
- Process Cell Sciences, Biologics Process R&D, Merck & Co., Inc., Kenilworth, NJ, USA
| | - Michael Betenbaugh
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Zhimei Du
- Process Cell Sciences, Biologics Process R&D, Merck & Co., Inc., Kenilworth, NJ, USA
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48
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Conjugation of Palbociclib with MHI-148 Has an Increased Cytotoxic Effect for Breast Cancer Cells and an Altered Mechanism of Action. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27030880. [PMID: 35164144 PMCID: PMC8840619 DOI: 10.3390/molecules27030880] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 01/13/2022] [Accepted: 01/21/2022] [Indexed: 11/16/2022]
Abstract
The CDK4/6 inhibitor palbociclib, combined with endocrine therapy, has been shown to be effective in postmenopausal women with estrogen receptor-positive, HER2-negative advanced or metastatic breast cancer. However, palbociclib is not as effective in the highly aggressive, triple-negative breast cancer that lacks sensitivity to chemotherapy or endocrine therapy. We hypothesized that conjugation of the near-infrared dye MHI-148 with palbociclib can produce a potential theranostic in triple-negative, as well as estrogen receptor-positive, breast cancer cells. In our study, the conjugate was found to have enhanced activity in all mammalian cell lines tested in vitro. However, the conjugate was cytotoxic and did not induce G1 cell cycle arrest in breast cancer cells, suggesting its mechanism of action differs from the parent compound palbociclib. The study highlights the importance of investigating the mechanism of conjugates of near-infrared dyes to therapeutic compounds, as conjugation can potentially result in a change of mechanism or target, with an enhanced cytotoxic effect in this case.
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49
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Zhu B, Zhong W, Cao X, Pan G, Xu M, Zheng J, Chen H, Feng X, Luo C, Lu C, Xiao J, Lin W, Lai C, Li M, Du X, Yi Q, Yan D. Loss of miR-31-5p drives hematopoietic stem cell malignant transformation and restoration eliminates leukemia stem cells in mice. Sci Transl Med 2022; 14:eabh2548. [PMID: 35080912 DOI: 10.1126/scitranslmed.abh2548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Leukemia stem cells (LSCs) propagate leukemia and are responsible for the high frequency of relapse of treated patients. The ability to target LSCs remains elusive, indicating a need to understand the underlying mechanism of LSC formation. Here, we report that miR-31-5p is reduced or undetectable in human LSCs compared to hematopoietic stem progenitor cells (HSPCs). Inhibition of miR-31-5p in HSPCs promotes the expression of its target gene FIH, encoding FIH [factor inhibiting hypoxia-inducing factor 1α (HIF-1α)], to suppress HIF-1α signaling. Increased FIH resulted in a switch from glycolysis to oxidative phosphorylation (OXPHOS) as the predominant mode of energy metabolism and increased the abundance of the oncometabolite fumarate. Increased fumarate promoted the conversion of HSPCs to LSCs and initiated myeloid leukemia-like disease in NOD-Prkdcscid IL2rgtm1/Bcgen (B-NDG) mice. We further demonstrated that miR-31-5p inhibited long- and short-term hematopoietic stem cells with a high frequency of LSCs. In combination with the chemotherapeutic agent Ara-C (cytosine arabinoside), restoration of miR-31-5p using G7 poly (amidoamine) nanosized dendriplex encapsulating miR-31-5p eliminated LSCs and inhibited acute myeloid leukemia (AML) progression in patient-derived xenograft mouse models. These results demonstrated a mechanism of HSC malignant transformation through altered energy metabolism and provided a potential therapeutic strategy to treat patients with AML.
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Affiliation(s)
- Biying Zhu
- MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou 510632, China
| | - Wenbin Zhong
- MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou 510632, China
| | - Xiuye Cao
- MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou 510632, China
| | - Guoping Pan
- MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou 510632, China
| | - Mengyang Xu
- MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou 510632, China
| | - Jie Zheng
- MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou 510632, China
| | - Huanzhao Chen
- MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou 510632, China
| | - Xiaoqin Feng
- Hematology and Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Chengwei Luo
- Department of Hematology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510000, China
| | - Chen Lu
- MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou 510632, China
| | - Jie Xiao
- MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou 510632, China
| | - Weize Lin
- MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou 510632, China
| | - Chaofeng Lai
- MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou 510632, China
| | - Mingchuan Li
- MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou 510632, China
| | - Xin Du
- Department of Hematology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510000, China
| | - Qing Yi
- Cancer Center, Houston Methodist Research Institute, Houston, TX 77030, USA
| | - Daoguang Yan
- MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou 510632, China
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50
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Abstract
Cyclin-dependent kinases 4 and 6 (CDK4 and CDK6) and their activating partners, D-type cyclins, link the extracellular environment with the core cell cycle machinery. Constitutive activation of cyclin D–CDK4/6 represents the driving force of tumorigenesis in several cancer types. Small-molecule inhibitors of CDK4/6 have been used with great success in the treatment of hormone receptor–positive breast cancers and are in clinical trials for many other tumor types. Unexpectedly, recent work indicates that inhibition of CDK4/6 affects a wide range of cellular functions such as tumor cell metabolism and antitumor immunity. We discuss how recent advances in understanding CDK4/6 biology are opening new avenues for the future use of cyclin D–CDK4/6 inhibitors in cancer treatment.
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Affiliation(s)
- Anne Fassl
- Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Yan Geng
- Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Piotr Sicinski
- Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA
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