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Elbialy A, Sood A, Wang SJ, Wang P, Fadiel A, Parwani AV, Huang S, Shvets G, Putluri N, Li J, Liu X. Unveiling racial disparities in prostate cancer using an integrative genomic and transcriptomic analysis. CELL INSIGHT 2025; 4:100238. [PMID: 40104216 PMCID: PMC11914995 DOI: 10.1016/j.cellin.2025.100238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 02/02/2025] [Accepted: 02/03/2025] [Indexed: 03/20/2025]
Abstract
Prostate cancer exhibits significant racial disparities, with African American (AA) individuals showing ∼64% higher incidence and 2.3 times greater mortality rates compared to their Caucasian (CA) counterparts. Understanding the complex interplay of genetic, environmental, lifestyle, socioeconomic, and healthcare access factors is crucial for developing effective interventions to reduce this disproportionate burden. This study aims to uncover the genetic and transcriptomic differences driving these disparities through a comprehensive analysis using RNA sequencing (RNA-seq) and exome sequencing of prostate cancer tissues from both Black and White patients. Our transcriptomics analysis revealed enhanced activity in pathways linked to immune response and cellular interactions in AA prostate cancer samples, with notable regulation by histone-associated transcription factors (HIST1H1A, HIST1H1D, and HIST1H1B) suggests potential involvement of histone modification mechanisms. Additionally, pseudogenes and long non-coding RNAs (lncRNAs) among the regulated genes indicate non-coding elements' role in these disparities. Exome sequencing identified unique variants in AA patient samples within key genes, including TP73 (tumor suppression), XYLB (metabolism), ALDH4A1 (oxidative stress), PTPRB (cellular signaling), and HLA-DRB5 (immune response). These genetic variations likely contribute to disease progression and therapy response disparities. This study highlights the importance of considering genetic and epigenetic variations in developing tailored therapeutic approaches to improve treatment efficacy and reduce mortality rates across diverse populations.
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Affiliation(s)
- Abdalla Elbialy
- OSU Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA
- Computational Oncology Unit, The University of Chicago Comprehensive Cancer Center, 900 E 57th Street, KCBD Bldg., STE 4144, Chicago, IL, 60637, USA
| | - Akshay Sood
- OSU Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA
- Department of Urology, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA
| | - Shang-Jui Wang
- OSU Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA
- Department of Radiation Oncology, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA
| | - Peng Wang
- OSU Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA
- Department of Medicine, College of Medicine, The Ohio State University, Columbus, OH, 3210, USA
| | - Ahmed Fadiel
- Computational Oncology Unit, The University of Chicago Comprehensive Cancer Center, 900 E 57th Street, KCBD Bldg., STE 4144, Chicago, IL, 60637, USA
| | - Anil V Parwani
- OSU Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA
- Departments of Pathology, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA
| | - Steven Huang
- School of Applied and Engineering Physics, Cornell University, Ithaca, NY, 14850, USA
| | - Gennady Shvets
- School of Applied and Engineering Physics, Cornell University, Ithaca, NY, 14850, USA
| | - Nagireddy Putluri
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Jenny Li
- OSU Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA
- Departments of Pathology, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA
| | - Xuefeng Liu
- OSU Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA
- Departments of Pathology, Urology, and Radiation Oncology, College of Medicine, The Ohio StateUniversity, Columbus, OH, 43210, USA
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Schaaf RE, Quirke JCK, Ghavami M, Tonogai EJ, Lee HY, Barlock SL, Trzupek TR, Abo KR, Rees MG, Ronan MM, Roth JA, Hergenrother PJ. Identification of a Selective Anticancer Agent from a Collection of Complex-And-Diverse Compounds Synthesized from Stevioside. J Am Chem Soc 2025; 147:10647-10661. [PMID: 40070033 DOI: 10.1021/jacs.5c00919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/27/2025]
Abstract
Compounds constructed by distorting the ring systems of natural products serve as a ready source of complex and diverse molecules, useful for a variety of applications. Herein is presented the use of the diterpenoids steviol and isosteviol as starting points for the construction of >50 new compounds through this complexity-to-diversity approach, featuring novel ring system distortions and a noteworthy thallium(III) nitrate (TTN)-mediated ring fusion. Evaluation of this collection identified SteviX4 as a potent and selective anticancer compound, inducing cell death at low nanomolar concentrations against some cancer cell lines in culture, compared to micromolar activity against others. SteviX4 induces ferroptotic cell death in susceptible cell lines, and target identification experiments reveal SteviX4 acts as an inhibitor of glutathione peroxidase 4 (GPX4), a critical protein that protects cancer cells against ferroptosis. In its induction of cell death, SteviX4 displays enhanced cell line selectivity relative to most known GPX4 inhibitors. SteviX4 was used to reveal dependency on GPX4 as a vulnerability of certain cancer cell lines, not tied to any one type of cancer, suggesting GPX4 inhibition as a cancer type-agnostic anticancer strategy. With its high fraction of sp3-hybridized carbons and considerable cell line selectivity and potency, SteviX4 is unique among GPX4 inhibitors, serving as an outstanding probe compound and basis for further translational development.
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Affiliation(s)
- Rachel E Schaaf
- Department of Chemistry, Cancer Center at Illinois, Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States
| | - Jonathan C K Quirke
- Department of Chemistry, Cancer Center at Illinois, Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States
| | - Maryam Ghavami
- Department of Chemistry, Cancer Center at Illinois, Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States
| | - Emily J Tonogai
- Department of Chemistry, Cancer Center at Illinois, Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States
| | - Hyang Yeon Lee
- Department of Chemistry, Cancer Center at Illinois, Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States
| | - Samantha L Barlock
- Department of Chemistry, Cancer Center at Illinois, Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States
| | - Thomas R Trzupek
- Department of Chemistry, Cancer Center at Illinois, Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States
| | - Kyle R Abo
- Department of Chemistry, Cancer Center at Illinois, Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States
| | - Matthew G Rees
- Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States
| | - Melissa M Ronan
- Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States
| | - Jennifer A Roth
- Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States
| | - Paul J Hergenrother
- Department of Chemistry, Cancer Center at Illinois, Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States
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Zanrè V, Bellinato F, Cardile A, Passarini C, Di Bella S, Menegazzi M. BRAF-Mutated Melanoma Cell Lines Develop Distinct Molecular Signatures After Prolonged Exposure to AZ628 or Dabrafenib: Potential Benefits of the Antiretroviral Treatments Cabotegravir or Doravirine on BRAF-Inhibitor-Resistant Cells. Int J Mol Sci 2024; 25:11939. [PMID: 39596009 PMCID: PMC11593403 DOI: 10.3390/ijms252211939] [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: 10/19/2024] [Revised: 10/31/2024] [Accepted: 11/05/2024] [Indexed: 11/28/2024] Open
Abstract
Melanoma is an aggressive cancer characterized by rapid growth, early metastasis, and poor prognosis, with resistance to current therapies being a significant issue. BRAF mutations drive uncontrolled cell division by activating the MAPK pathway. In this study, A375 and FO-1, BRAF-mutated melanoma cell lines, were treated for 4-5 months with RAF inhibitor dabrafenib or AZ628, leading to drug resistance over time. The resistant cells showed altered molecular signatures, with differences in cell cycle regulation and the propensity of cell death. Dabrafenib-resistant cells maintained high proliferative activity, while AZ628-resistant cells, especially A375 cells, exhibited slow-cycling, and a senescent-like phenotype with high susceptibility to ferroptosis, a form of cell death driven by iron. Antiretroviral drugs doravirine and cabotegravir, known for their effects on human endogenous retroviruses, were tested for their impact on these resistant melanoma cells. Both drugs reduced cell viability and colony formation in resistant cell lines. Doravirine was particularly effective in reactivating apoptosis and reducing cell growth in highly proliferative resistant cells by increasing tumor-suppressor proteins p16Ink4a and p27Kip1. These findings suggest that antiretroviral drugs can influence apoptosis and cell proliferation in RAF-inhibitor-resistant melanoma cells, offering potential therapeutic strategies for overcoming drug resistance.
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Affiliation(s)
- Valentina Zanrè
- Section of Biochemistry, Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Strada Le Grazie 8, 37134 Verona, Italy; (V.Z.)
| | - Francesco Bellinato
- Section of Dermatology and Venereology, Department of Medicine, University of Verona, Piazzale Stefani 1, 37126 Verona, Italy;
| | - Alessia Cardile
- Section of Biochemistry, Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Strada Le Grazie 8, 37134 Verona, Italy; (V.Z.)
| | - Carlotta Passarini
- Section of Biochemistry, Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Strada Le Grazie 8, 37134 Verona, Italy; (V.Z.)
| | - Stefano Di Bella
- Clinical Department of Medical, Surgical and Health Sciences, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy;
| | - Marta Menegazzi
- Section of Biochemistry, Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Strada Le Grazie 8, 37134 Verona, Italy; (V.Z.)
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Poliaková Turan M, Riedo R, Medo M, Pozzato C, Friese-Hamim M, Koch JP, Coggins SA, Li Q, Kim B, Albers J, Aebersold DM, Zamboni N, Zimmer Y, Medová M. E2F1-Associated Purine Synthesis Pathway Is a Major Component of the MET-DNA Damage Response Network. CANCER RESEARCH COMMUNICATIONS 2024; 4:1863-1880. [PMID: 38957115 PMCID: PMC11288008 DOI: 10.1158/2767-9764.crc-23-0370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 05/03/2024] [Accepted: 06/25/2024] [Indexed: 07/04/2024]
Abstract
Various lines of investigation support a signaling interphase shared by receptor tyrosine kinases and the DNA damage response. However, the underlying network nodes and their contribution to the maintenance of DNA integrity remain unknown. We explored MET-related metabolic pathways in which interruption compromises proper resolution of DNA damage. Discovery metabolomics combined with transcriptomics identified changes in pathways relevant to DNA repair following MET inhibition (METi). METi by tepotinib was associated with the formation of γH2AX foci and with significant alterations in major metabolic circuits such as glycolysis, gluconeogenesis, and purine, pyrimidine, amino acid, and lipid metabolism. 5'-Phosphoribosyl-N-formylglycinamide, a de novo purine synthesis pathway metabolite, was consistently decreased in in vitro and in vivo MET-dependent models, and METi-related depletion of dNTPs was observed. METi instigated the downregulation of critical purine synthesis enzymes including phosphoribosylglycinamide formyltransferase, which catalyzes 5'-phosphoribosyl-N-formylglycinamide synthesis. Genes encoding these enzymes are regulated through E2F1, whose levels decrease upon METi in MET-driven cells and xenografts. Transient E2F1 overexpression prevented dNTP depletion and the concomitant METi-associated DNA damage in MET-driven cells. We conclude that DNA damage following METi results from dNTP reduction via downregulation of E2F1 and a consequent decline of de novo purine synthesis. SIGNIFICANCE Maintenance of genome stability prevents disease and affiliates with growth factor receptor tyrosine kinases. We identified de novo purine synthesis as a pathway in which key enzymatic players are regulated through MET receptor and whose depletion via MET targeting explains MET inhibition-associated formation of DNA double-strand breaks. The mechanistic importance of MET inhibition-dependent E2F1 downregulation for interference with DNA integrity has translational implications for MET-targeting-based treatment of malignancies.
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Affiliation(s)
- Michaela Poliaková Turan
- Department of Radiation Oncology, Inselspital Bern University Hospital, Bern, Switzerland.
- Department for BioMedical Research, Radiation Oncology, University of Bern, Bern, Switzerland.
- Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
| | - Rahel Riedo
- Department of Radiation Oncology, Inselspital Bern University Hospital, Bern, Switzerland.
- Department for BioMedical Research, Radiation Oncology, University of Bern, Bern, Switzerland.
| | - Matúš Medo
- Department of Radiation Oncology, Inselspital Bern University Hospital, Bern, Switzerland.
- Department for BioMedical Research, Radiation Oncology, University of Bern, Bern, Switzerland.
| | - Chiara Pozzato
- Department of Radiation Oncology, Inselspital Bern University Hospital, Bern, Switzerland.
- Department for BioMedical Research, Radiation Oncology, University of Bern, Bern, Switzerland.
| | - Manja Friese-Hamim
- Corporate Animal Using Vendor and Vivarium Governance (SQ-AV), Corporate Sustainability, Quality, Trade Compliance (SQ), Animal Affairs (SQ-A), The Healthcare Business of Merck KGaA, Darmstadt, Germany.
| | - Jonas P. Koch
- Department of Radiation Oncology, Inselspital Bern University Hospital, Bern, Switzerland.
- Department for BioMedical Research, Radiation Oncology, University of Bern, Bern, Switzerland.
- Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
| | - Si’Ana A. Coggins
- Center for Drug Discovery, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia.
| | - Qun Li
- Center for Drug Discovery, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia.
| | - Baek Kim
- Center for Drug Discovery, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia.
- College of Pharmacy, Kyung-Hee University, Seoul, South Korea.
| | - Joachim Albers
- Research Unit Oncology, The Healthcare Business of Merck KGaA, Darmstadt, Germany.
| | - Daniel M. Aebersold
- Department of Radiation Oncology, Inselspital Bern University Hospital, Bern, Switzerland.
- Department for BioMedical Research, Radiation Oncology, University of Bern, Bern, Switzerland.
| | - Nicola Zamboni
- Institute of Molecular Systems Biology, ETH Zürich, Zürich, Switzerland.
- PHRT Swiss Multi-Omics Center, Zurich, Switzerland.
| | - Yitzhak Zimmer
- Department of Radiation Oncology, Inselspital Bern University Hospital, Bern, Switzerland.
- Department for BioMedical Research, Radiation Oncology, University of Bern, Bern, Switzerland.
| | - Michaela Medová
- Department of Radiation Oncology, Inselspital Bern University Hospital, Bern, Switzerland.
- Department for BioMedical Research, Radiation Oncology, University of Bern, Bern, Switzerland.
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5
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Zhai J, Liu Y, Ji W, Huang X, Wang P, Li Y, Li H, Wong AHH, Zhou X, Chen P, Wang L, Yang N, Chen C, Chen H, Mak PI, Deng CX, Martins R, Yang M, Ho TY, Yi S, Yao H, Jia Y. Drug screening on digital microfluidics for cancer precision medicine. Nat Commun 2024; 15:4363. [PMID: 38778087 PMCID: PMC11111680 DOI: 10.1038/s41467-024-48616-3] [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: 06/20/2023] [Accepted: 05/08/2024] [Indexed: 05/25/2024] Open
Abstract
Drug screening based on in-vitro primary tumor cell culture has demonstrated potential in personalized cancer diagnosis. However, the limited number of tumor cells, especially from patients with early stage cancer, has hindered the widespread application of this technique. Hence, we developed a digital microfluidic system for drug screening using primary tumor cells and established a working protocol for precision medicine. Smart control logic was developed to increase the throughput of the system and decrease its footprint to parallelly screen three drugs on a 4 × 4 cm2 chip in a device measuring 23 × 16 × 3.5 cm3. We validated this method in an MDA-MB-231 breast cancer xenograft mouse model and liver cancer specimens from patients, demonstrating tumor suppression in mice/patients treated with drugs that were screened to be effective on individual primary tumor cells. Mice treated with drugs screened on-chip as ineffective exhibited similar results to those in the control groups. The effective drug identified through on-chip screening demonstrated consistency with the absence of mutations in their related genes determined via exome sequencing of individual tumors, further validating this protocol. Therefore, this technique and system may promote advances in precision medicine for cancer treatment and, eventually, for any disease.
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Affiliation(s)
- Jiao Zhai
- State Key Laboratory of Analog and Mixed-Signal VLSI, Institute of Microelectronics, University of Macau, Macau SAR, China
- Department of Biomedical Sciences, and Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong SAR, China
| | - Yingying Liu
- State Key Laboratory of Analog and Mixed-Signal VLSI, Institute of Microelectronics, University of Macau, Macau SAR, China
- Faculty of Science and Technology, University of Macau, Macau SAR, China
| | - Weiqing Ji
- School of Computer and Communication Engineering, University of Science and Technology Beijing, Beijing, China
| | - Xinru Huang
- Liver Transplantation Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Ping Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yunyi Li
- State Key Laboratory of Analog and Mixed-Signal VLSI, Institute of Microelectronics, University of Macau, Macau SAR, China
| | - Haoran Li
- State Key Laboratory of Analog and Mixed-Signal VLSI, Institute of Microelectronics, University of Macau, Macau SAR, China
- Faculty of Science and Technology, University of Macau, Macau SAR, China
| | - Ada Hang-Heng Wong
- MoE Frontiers Science Center for Precision Oncology, University of Macau, Macau SAR, China
| | - Xiong Zhou
- State Key Laboratory of Analog and Mixed-Signal VLSI, Institute of Microelectronics, University of Macau, Macau SAR, China
- College of electrical and information engineering, Hunan University, Changsha, China
| | - Ping Chen
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau SAR, China
| | - Lianhong Wang
- College of electrical and information engineering, Hunan University, Changsha, China
| | - Ning Yang
- State Key Laboratory of Analog and Mixed-Signal VLSI, Institute of Microelectronics, University of Macau, Macau SAR, China
- Department of Electronic Information Engineering, Jiangsu University, Zhenjiang, China
| | - Chi Chen
- Liver Transplantation Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Haitian Chen
- Liver Transplantation Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Pui-In Mak
- State Key Laboratory of Analog and Mixed-Signal VLSI, Institute of Microelectronics, University of Macau, Macau SAR, China
- Faculty of Science and Technology, University of Macau, Macau SAR, China
| | - Chu-Xia Deng
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau SAR, China
| | - Rui Martins
- State Key Laboratory of Analog and Mixed-Signal VLSI, Institute of Microelectronics, University of Macau, Macau SAR, China
- Faculty of Science and Technology, University of Macau, Macau SAR, China
- On leave from Instituto Superior Tecnico, Universidade de Lisboa, Lisboa, Portugal
| | - Mengsu Yang
- Department of Biomedical Sciences, and Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong SAR, China
| | - Tsung-Yi Ho
- Department of Compute Science and Engineering, The Chinese University of Hong Kong, Hong Kong, China
| | - Shuhong Yi
- Liver Transplantation Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
| | - Hailong Yao
- School of Computer and Communication Engineering, University of Science and Technology Beijing, Beijing, China.
| | - Yanwei Jia
- State Key Laboratory of Analog and Mixed-Signal VLSI, Institute of Microelectronics, University of Macau, Macau SAR, China.
- Faculty of Science and Technology, University of Macau, Macau SAR, China.
- MoE Frontiers Science Center for Precision Oncology, University of Macau, Macau SAR, China.
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Yin H, Tang Q, Xia H, Bi F. Targeting RAF dimers in RAS mutant tumors: From biology to clinic. Acta Pharm Sin B 2024; 14:1895-1923. [PMID: 38799634 PMCID: PMC11120325 DOI: 10.1016/j.apsb.2024.02.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 01/02/2024] [Accepted: 02/20/2024] [Indexed: 05/29/2024] Open
Abstract
RAS mutations occur in approximately 30% of tumors worldwide and have a poor prognosis due to limited therapies. Covalent targeting of KRAS G12C has achieved significant success in recent years, but there is still a lack of efficient therapeutic approaches for tumors with non-G12C KRAS mutations. A highly promising approach is to target the MAPK pathway downstream of RAS, with a particular focus on RAF kinases. First-generation RAF inhibitors have been authorized to treat BRAF mutant tumors for over a decade. However, their use in RAS-mutated tumors is not recommended due to the paradoxical ERK activation mainly caused by RAF dimerization. To address the issue of RAF dimerization, type II RAF inhibitors have emerged as leading candidates. Recent clinical studies have shown the initial effectiveness of these agents against RAS mutant tumors. Promisingly, type II RAF inhibitors in combination with MEK or ERK inhibitors have demonstrated impressive efficacy in RAS mutant tumors. This review aims to clarify the importance of RAF dimerization in cellular signaling and resistance to treatment in tumors with RAS mutations, as well as recent progress in therapeutic approaches to address the problem of RAF dimerization in RAS mutant tumors.
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Affiliation(s)
- Huanhuan Yin
- Division of Abdominal Cancer, Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Qiulin Tang
- Division of Abdominal Cancer, Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Hongwei Xia
- Division of Abdominal Cancer, Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Feng Bi
- Division of Abdominal Cancer, Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu 610041, China
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7
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Fernandes M, Hoggard B, Jamme P, Paget S, Truong M, Grégoire V, Vinchent A, Descarpentries C, Morabito A, Stanislovas J, Farage E, Meneboo J, Sebda S, Bouchekioua‐Bouzaghou K, Nollet M, Humez S, Perera T, Fromme P, Grumolato L, Figeac M, Copin M, Tulasne D, Cortot AB, Kermorgant S, Kherrouche Z. MET exon 14 skipping mutation is a hepatocyte growth factor (HGF)-dependent oncogenic driver in vitro and in humanised HGF knock-in mice. Mol Oncol 2023; 17:2257-2274. [PMID: 36799689 PMCID: PMC10620121 DOI: 10.1002/1878-0261.13397] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 12/27/2022] [Accepted: 02/16/2023] [Indexed: 02/18/2023] Open
Abstract
Exon skipping mutations of the MET receptor tyrosine kinase (METex14), increasingly reported in cancers, occur in 3-4% of non-small-cell lung cancer (NSCLC). Only 50% of patients have a beneficial response to treatment with MET-tyrosine kinase inhibitors (TKIs), underlying the need to understand the mechanism of METex14 oncogenicity and sensitivity to TKIs. Whether METex14 is a driver mutation and whether it requires hepatocyte growth factor (HGF) for its oncogenicity in a range of in vitro functions and in vivo has not been fully elucidated from previous preclinical models. Using CRISPR/Cas9, we developed a METex14/WT isogenic model in nontransformed human lung cells and report that the METex14 single alteration was sufficient to drive MET-dependent in vitro anchorage-independent survival and motility and in vivo tumorigenesis, sensitising tumours to MET-TKIs. However, we also show that human HGF (hHGF) is required, as demonstrated in vivo using a humanised HGF knock-in strain of mice and further detected in tumour cells of METex14 NSCLC patient samples. Our results also suggest that METex14 oncogenicity is not a consequence of an escape from degradation in our cell model. Thus, we developed a valuable model for preclinical studies and present results that have potential clinical implication.
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Affiliation(s)
- Marie Fernandes
- Univ. Lille, CNRS, Inserm, CHU LilleInstitut Pasteur de Lille, UMR9020 – UMR1277 - Canther – Cancer Heterogeneity, Plasticity and Resistance to TherapiesFrance
| | | | - Philippe Jamme
- Univ. Lille, CNRS, Inserm, CHU LilleInstitut Pasteur de Lille, UMR9020 – UMR1277 - Canther – Cancer Heterogeneity, Plasticity and Resistance to TherapiesFrance
| | - Sonia Paget
- Univ. Lille, CNRS, Inserm, CHU LilleInstitut Pasteur de Lille, UMR9020 – UMR1277 - Canther – Cancer Heterogeneity, Plasticity and Resistance to TherapiesFrance
| | - Marie‐José Truong
- Univ. Lille, CNRS, Inserm, CHU LilleInstitut Pasteur de Lille, UMR9020 – UMR1277 - Canther – Cancer Heterogeneity, Plasticity and Resistance to TherapiesFrance
| | | | - Audrey Vinchent
- Univ. Lille, CNRS, Inserm, CHU LilleInstitut Pasteur de Lille, UMR9020 – UMR1277 - Canther – Cancer Heterogeneity, Plasticity and Resistance to TherapiesFrance
| | | | - Angela Morabito
- Univ. Lille, CNRS, Inserm, CHU LilleInstitut Pasteur de Lille, UMR9020 – UMR1277 - Canther – Cancer Heterogeneity, Plasticity and Resistance to TherapiesFrance
| | | | - Enoir Farage
- Barts Cancer InstituteQueen Mary University of LondonUK
| | - Jean‐Pascal Meneboo
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, US 41 - UAR 2014 - PLBS, LilleFrance
| | - Shéhérazade Sebda
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, US 41 - UAR 2014 - PLBS, LilleFrance
| | | | - Marie Nollet
- Barts Cancer InstituteQueen Mary University of LondonUK
| | - Sarah Humez
- Univ. Lille, CNRS, Inserm, CHU LilleInstitut Pasteur de Lille, UMR9020 – UMR1277 - Canther – Cancer Heterogeneity, Plasticity and Resistance to TherapiesFrance
- Univ LilleDepartment of Pathology, CHU LilleFrance
| | | | - Paul Fromme
- Department of Mechanical EngineeringUniversity College LondonUK
| | - Luca Grumolato
- Univ Rouen Normandie, Inserm, NorDiC UMR 1239, 76000 RouenFrance
| | - Martin Figeac
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, US 41 - UAR 2014 - PLBS, LilleFrance
| | - Marie‐Christine Copin
- Univ. Lille, CNRS, Inserm, CHU LilleInstitut Pasteur de Lille, UMR9020 – UMR1277 - Canther – Cancer Heterogeneity, Plasticity and Resistance to TherapiesFrance
- Univ LilleDepartment of Pathology, CHU LilleFrance
| | - David Tulasne
- Univ. Lille, CNRS, Inserm, CHU LilleInstitut Pasteur de Lille, UMR9020 – UMR1277 - Canther – Cancer Heterogeneity, Plasticity and Resistance to TherapiesFrance
| | - Alexis B. Cortot
- Univ. Lille, CNRS, Inserm, CHU LilleInstitut Pasteur de Lille, UMR9020 – UMR1277 - Canther – Cancer Heterogeneity, Plasticity and Resistance to TherapiesFrance
- Univ. LilleThoracic Oncology Department, CHU LilleFrance
| | | | - Zoulika Kherrouche
- Univ. Lille, CNRS, Inserm, CHU LilleInstitut Pasteur de Lille, UMR9020 – UMR1277 - Canther – Cancer Heterogeneity, Plasticity and Resistance to TherapiesFrance
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8
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Altintas DM, Comoglio PM. An Observatory for the MET Oncogene: A Guide for Targeted Therapies. Cancers (Basel) 2023; 15:4672. [PMID: 37760640 PMCID: PMC10526818 DOI: 10.3390/cancers15184672] [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: 08/31/2023] [Revised: 09/13/2023] [Accepted: 09/20/2023] [Indexed: 09/29/2023] Open
Abstract
The MET proto-oncogene encodes a pivotal tyrosine kinase receptor, binding the hepatocyte growth factor (HGF, also known as scatter factor, SF) and governing essential biological processes such as organogenesis, tissue repair, and angiogenesis. The pleiotropic physiological functions of MET explain its diverse role in cancer progression in a broad range of tumors; genetic/epigenetic alterations of MET drive tumor cell dissemination, metastasis, and acquired resistance to conventional and targeted therapies. Therefore, targeting MET emerged as a promising strategy, and many efforts were devoted to identifying the optimal way of hampering MET signaling. Despite encouraging results, however, the complexity of MET's functions in oncogenesis yields intriguing observations, fostering a humbler stance on our comprehension. This review explores recent discoveries concerning MET alterations in cancer, elucidating their biological repercussions, discussing therapeutic avenues, and outlining future directions. By contextualizing the research question and articulating the study's purpose, this work navigates MET biology's intricacies in cancer, offering a comprehensive perspective.
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Affiliation(s)
| | - Paolo M. Comoglio
- IFOM ETS—The AIRC Institute of Molecular Oncology, 20139 Milano, Italy;
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9
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Trastulla L, Savino A, Beltrao P, Ciriano IC, Fenici P, Garnett MJ, Guerini I, Bigas NL, Mattaj I, Petsalaki E, Riva L, Tape CJ, Leeuwen JV, Sharma S, Vazquez F, Iorio F. Highlights from the 1st European cancer dependency map symposium and workshop. FEBS Lett 2023; 597:1921-1927. [PMID: 37487655 DOI: 10.1002/1873-3468.14699] [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: 07/06/2023] [Revised: 07/10/2023] [Accepted: 07/13/2023] [Indexed: 07/26/2023]
Abstract
The systematic identification of tumour vulnerabilities through perturbational experiments on cancer models, including genome editing and drug screens, is playing a crucial role in combating cancer. This collective effort is known as the Cancer Dependency Map (DepMap). The 1st European Cancer Dependency Map Symposium (EuroDepMap), held in Milan last May, featured talks, a roundtable discussion, and a poster session, showcasing the latest discoveries and future challenges related to the DepMap. The symposium aimed to facilitate interactions among participants across Europe, encourage idea exchange with leading experts, and present their work and future projects. Importantly, it sparked discussions on future endeavours, such as screening more complex cancer models and accounting for tumour evolution.
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Affiliation(s)
| | | | - Pedro Beltrao
- Institute of Molecular Systems Biology, ETH Zürich, Zurich, Switzerland
| | | | | | | | | | | | | | | | | | | | | | | | - Francisca Vazquez
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
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10
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Daneshdoust D, Yin M, Luo M, Sundi D, Dang Y, Lee C, Li J, Liu X. Conditional Reprogramming Modeling of Bladder Cancer for Clinical Translation. Cells 2023; 12:1714. [PMID: 37443748 PMCID: PMC10341071 DOI: 10.3390/cells12131714] [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: 05/04/2023] [Revised: 06/09/2023] [Accepted: 06/21/2023] [Indexed: 07/15/2023] Open
Abstract
The use of advanced preclinical models has become increasingly important in drug development. This is particularly relevant in bladder cancer, where the global burden of disease is quite high based on prevalence and a relatively high rate of lethality. Predictive tools to select patients who will be responsive to invasive or morbid therapies (chemotherapy, radiotherapy, immunotherapy, and/or surgery) are largely absent. Patient-derived and clinically relevant models including patient-derived xenografts (PDX), organoids, and conditional reprogramming (CR) of cell cultures efficiently generate numerous models and are being used in both basic and translational cancer biology. These CR cells (CRCs) can be reprogrammed to maintain a highly proliferative state and reproduce the genomic and histological characteristics of the parental tissue. Therefore, CR technology may be a clinically relevant model to test and predict drug sensitivity, conduct gene profile analysis and xenograft research, and undertake personalized medicine. This review discusses studies that have utilized CR technology to conduct bladder cancer research.
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Affiliation(s)
- Danyal Daneshdoust
- Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA (M.L.)
| | - Ming Yin
- Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA (M.L.)
- Department of Medicine, Wexner Medical Center, Ohio State University, Columbus, OH 43210, USA
| | - Mingjue Luo
- Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA (M.L.)
| | - Debasish Sundi
- Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA (M.L.)
- Department of Urology, Wexner Medical Center, Ohio State University, Columbus, OH 43210, USA
| | - Yongjun Dang
- Center for Novel Target and Therapeutic Intervention, Chongqing Medical University, Chongqing 400016, China
| | - Cheryl Lee
- Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA (M.L.)
- Department of Urology, Wexner Medical Center, Ohio State University, Columbus, OH 43210, USA
| | - Jenny Li
- Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA (M.L.)
| | - Xuefeng Liu
- Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA (M.L.)
- Departments of Pathology, Urology and Radiation Oncology, Wexner Medical Center, Ohio State University, Columbus, OH 43210, USA
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11
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An mTOR feedback loop mediates the 'flare' ('rebound') response to MET tyrosine kinase inhibition. Sci Rep 2023; 13:1378. [PMID: 36697438 PMCID: PMC9876934 DOI: 10.1038/s41598-023-28648-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 01/23/2023] [Indexed: 01/26/2023] Open
Abstract
Targeted therapy significantly impairs tumour growth but suffers from limitations, among which the 'flare' ('rebound') effect. Among cancers driven by tyrosine kinase receptors, those relying on alterations of the MET oncogene benefit from treatment by specific inhibitors. Previously, we reported that discontinuation of MET tyrosine kinase receptor inhibition causes 'rebound' activation of the oncogene, with a post-treatment transient hyperphosphorylation phase that culminates into a dramatic increase in cancer cell proliferation. The molecular mechanisms behind the 'MET burst' after treatment cessation are unknown but critically important for patients. Here we identify a positive feedback loop mediated by the AKT/mTOR pathway leading to (a) enhanced MET translation by activating p70S6K and 4EBP1 and (b) MET hyper-phosphorylation by inactivation of the tyrosine-phosphatase PTP1B. The latter effect is due to m-TOR-driven PTP1B phosphorylation of the inhibitory residues Ser50 and Ser378. These data provide in vitro evidence for the use of mTOR inhibitors to prevent the 'flare effect' in MET targeted therapy, with potential applicative ramifications for patient clinical management.
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12
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An oncogene addiction phosphorylation signature and its derived scores inform tumor responsiveness to targeted therapies. Cell Mol Life Sci 2022; 80:6. [PMID: 36494469 PMCID: PMC9734221 DOI: 10.1007/s00018-022-04634-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 11/08/2022] [Accepted: 11/14/2022] [Indexed: 12/13/2022]
Abstract
PURPOSE Oncogene addiction provides important therapeutic opportunities for precision oncology treatment strategies. To date the cellular circuitries associated with driving oncoproteins, which eventually establish the phenotypic manifestation of oncogene addiction, remain largely unexplored. Data suggest the DNA damage response (DDR) as a central signaling network that intersects with pathways associated with deregulated addicting oncoproteins with kinase activity in cancer cells. EXPERIMENTAL DESIGN: We employed a targeted mass spectrometry approach to systematically explore alterations in 116 phosphosites related to oncogene signaling and its intersection with the DDR following inhibition of the addicting oncogene alone or in combination with irradiation in MET-, EGFR-, ALK- or BRAF (V600)-positive cancer models. An NSCLC tissue pipeline combining patient-derived xenografts (PDXs) and ex vivo patient organotypic cultures has been established for treatment responsiveness assessment. RESULTS We identified an 'oncogene addiction phosphorylation signature' (OAPS) consisting of 8 protein phosphorylations (ACLY S455, IF4B S422, IF4G1 S1231, LIMA1 S490, MYCN S62, NCBP1 S22, P3C2A S259 and TERF2 S365) that are significantly suppressed upon targeted oncogene inhibition solely in addicted cell line models and patient tissues. We show that the OAPS is present in patient tissues and the OAPS-derived score strongly correlates with the ex vivo responses to targeted treatments. CONCLUSIONS We propose a score derived from OAPS as a quantitative measure to evaluate oncogene addiction of cancer cell samples. This work underlines the importance of protein phosphorylation assessment for patient stratification in precision oncology and corresponding identification of tumor subtypes sensitive to inhibition of a particular oncogene.
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13
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Gupta P, Strange K, Telange R, Guo A, Hatch H, Sobh A, Elie J, Carter AM, Totenhagen J, Tan C, Sonawane YA, Neuzil J, Natarajan A, Ovens AJ, Oakhill JS, Wiederhold T, Pacak K, Ghayee HK, Meijer L, Reddy S, Bibb JA. Genetic impairment of succinate metabolism disrupts bioenergetic sensing in adrenal neuroendocrine cancer. Cell Rep 2022; 40:111218. [PMID: 35977518 DOI: 10.1016/j.celrep.2022.111218] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 05/24/2022] [Accepted: 07/19/2022] [Indexed: 01/11/2023] Open
Abstract
Metabolic dysfunction mutations can impair energy sensing and cause cancer. Loss of function of the mitochondrial tricarboxylic acid (TCA) cycle enzyme subunit succinate dehydrogenase B (SDHB) results in various forms of cancer typified by pheochromocytoma (PC). Here we delineate a signaling cascade where the loss of SDHB induces the Warburg effect, triggers dysregulation of [Ca2+]i, and aberrantly activates calpain and protein kinase Cdk5, through conversion of its cofactor from p35 to p25. Consequently, aberrant Cdk5 initiates a phospho-signaling cascade where GSK3 inhibition inactivates energy sensing by AMP kinase through dephosphorylation of the AMP kinase γ subunit, PRKAG2. Overexpression of p25-GFP in mouse adrenal chromaffin cells also elicits this phosphorylation signaling and causes PC. A potent Cdk5 inhibitor, MRT3-007, reverses this phospho-cascade, invoking a senescence-like phenotype. This therapeutic approach halted tumor progression in vivo. Thus, we reveal an important mechanistic feature of metabolic sensing and demonstrate that its dysregulation underlies tumor progression in PC and likely other cancers.
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Affiliation(s)
- Priyanka Gupta
- Department of Surgery, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL 35233, USA
| | - Keehn Strange
- Department of Surgery, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL 35233, USA
| | - Rahul Telange
- Department of Hematology, St Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Ailan Guo
- Cell Signaling Technology, Danvers, MA 01923, USA
| | - Heather Hatch
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Amin Sobh
- Department of Medicine, Division of Hematology and Oncology, University of Florida, Gainesville, FL 32608, USA
| | - Jonathan Elie
- Perha Pharmaceuticals, Hôtel de Recherche, Perharidy Peninsula, 29680 Roscoff, France
| | - Angela M Carter
- Department of Surgery, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL 35233, USA
| | - John Totenhagen
- Department of Radiology, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL 35233, USA
| | - Chunfeng Tan
- UT Health Science Center at Houston, Department of Neurology, University of Texas McGovern Medical School, Houston, TX 77030, USA
| | - Yogesh A Sonawane
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Jiri Neuzil
- Institute of Biotechnology, Czech Academy of Sciences, Prague-West 252 50, Czech Republic; School of Pharmacy Medical Science, Griffith University, Southport, QLD 4222, Australia
| | - Amarnath Natarajan
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Ashley J Ovens
- Metabolic Signalling Laboratory, St Vincent's Institute of Medical Research, Fitzroy, VIC, Australia; Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, VIC, Australia
| | - Jonathan S Oakhill
- Metabolic Signalling Laboratory, St Vincent's Institute of Medical Research, Fitzroy, VIC, Australia; Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, VIC, Australia
| | | | - Karel Pacak
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
| | - Hans K Ghayee
- Department of Internal Medicine, Division of Endocrinology, University of Florida College of Medicine and Malcom Randall VA Medical Center, Gainesville, FL 32608, USA
| | - Laurent Meijer
- Perha Pharmaceuticals, Hôtel de Recherche, Perharidy Peninsula, 29680 Roscoff, France
| | - Sushanth Reddy
- Department of Surgery, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL 35233, USA
| | - James A Bibb
- Department of Surgery, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL 35233, USA; O'Neal Comprehensive Cancer Center and the Department of Neurobiology, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL 35233, USA.
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14
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Trastulla L, Noorbakhsh J, Vazquez F, McFarland J, Iorio F. Computational estimation of quality and clinical relevance of cancer cell lines. Mol Syst Biol 2022; 18:e11017. [PMID: 35822563 PMCID: PMC9277610 DOI: 10.15252/msb.202211017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 06/10/2022] [Accepted: 06/13/2022] [Indexed: 12/12/2022] Open
Abstract
Immortal cancer cell lines (CCLs) are the most widely used system for investigating cancer biology and for the preclinical development of oncology therapies. Pharmacogenomic and genome-wide editing screenings have facilitated the discovery of clinically relevant gene-drug interactions and novel therapeutic targets via large panels of extensively characterised CCLs. However, tailoring pharmacological strategies in a precision medicine context requires bridging the existing gaps between tumours and in vitro models. Indeed, intrinsic limitations of CCLs such as misidentification, the absence of tumour microenvironment and genetic drift have highlighted the need to identify the most faithful CCLs for each primary tumour while addressing their heterogeneity, with the development of new models where necessary. Here, we discuss the most significant limitations of CCLs in representing patient features, and we review computational methods aiming at systematically evaluating the suitability of CCLs as tumour proxies and identifying the best patient representative in vitro models. Additionally, we provide an overview of the applications of these methods to more complex models and discuss future machine-learning-based directions that could resolve some of the arising discrepancies.
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Affiliation(s)
| | - Javad Noorbakhsh
- Broad Institute of MIT and HarvardCambridgeMAUSA
- Present address:
Kojin TherapeuticsBostonMAUSA
| | - Francisca Vazquez
- Broad Institute of MIT and HarvardCambridgeMAUSA
- Department of Medical OncologyDana‐Farber Cancer InstituteBostonMAUSA
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15
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Hostallero DE, Li Y, Emad A. Looking at the BiG Picture: Incorporating bipartite graphs in drug response prediction. Bioinformatics 2022; 38:3609-3620. [PMID: 35674359 DOI: 10.1093/bioinformatics/btac383] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 04/17/2022] [Accepted: 06/01/2022] [Indexed: 12/15/2022] Open
Abstract
MOTIVATION The increasing number of publicly available databases containing drugs' chemical structures, their response in cell lines, and molecular profiles of the cell lines has garnered attention to the problem of drug response prediction. However, many existing methods do not fully leverage the information that is shared among cell lines and drugs with similar structure. As such, drug similarities in terms of cell line responses and chemical structures could prove to be useful in forming drug representations to improve drug response prediction accuracy. RESULTS We present two deep learning approaches, BiG-DRP and BiG-DRP+, for drug response prediction. Our models take advantage of the drugs' chemical structure and the underlying relationships of drugs and cell lines through a bipartite graph and a heterogenous graph convolutional network that incorporate sensitive and resistant cell line information in forming drug representations. Evaluation of our methods and other state-of-the-art models in different scenarios shows that incorporating this bipartite graph significantly improves the prediction performance. Additionally, genes that contribute significantly to the performance of our models also point to important biological processes and signaling pathways. Analysis of predicted drug response of patients' tumors using our model revealed important associations between mutations and drug sensitivity, illustrating the utility of our model in pharmacogenomics studies. AVAILABILITY AND IMPLEMENTATION An implementation of the algorithms in Python is provided in https://github.com/ddhostallero/BiG-DRP. SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.
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Affiliation(s)
- David Earl Hostallero
- Department of Electrical and Computer Engineering, McGill University, Montreal, QC H3A 0E9, Canada
- Mila, Quebec AI Institute, Montreal, QC H2S 3H1, Canada
| | - Yihui Li
- Department of Electrical and Computer Engineering, McGill University, Montreal, QC H3A 0E9, Canada
| | - Amin Emad
- Department of Electrical and Computer Engineering, McGill University, Montreal, QC H3A 0E9, Canada
- Mila, Quebec AI Institute, Montreal, QC H2S 3H1, Canada
- The Rosalind and Morris Goodman Cancer Institute, Montreal, QC H3A 1A3, Canada
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16
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De Herdt MJ, van der Steen B, Baatenburg de Jong RJ, Looijenga LHJ, Koljenović S, Hardillo JA. The Occurrence of MET Ectodomain Shedding in Oral Cancer and Its Potential Impact on the Use of Targeted Therapies. Cancers (Basel) 2022; 14:cancers14061491. [PMID: 35326642 PMCID: PMC8946088 DOI: 10.3390/cancers14061491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 02/18/2022] [Accepted: 03/10/2022] [Indexed: 02/01/2023] Open
Abstract
Simple Summary Head and neck cancer is the sixth most common cancer type worldwide, comprising tumors of the upper aero/digestive tract. Approximately 50% of these cancers originate in the oral cavity. Depending on disease stage, oral cancer patients are treated with single-modality surgery, or in combination with radiotherapy with or without chemotherapy. Despite advances in these modalities, the 5-year survival rate is merely 50%. Therefore, implementation of targeted therapies, directed against signaling molecules, has gained attention. One potential target is the MET protein, which can be present on the surface of cancer cells, orchestrating aggressive behavior. As cancer cells can shed the extracellular part of MET from their surface, it is important to identify for MET positive patients whether they possess the entire and/or only the intracellular part of the receptor to assess whether targeted therapies directed against the extracellular, intracellular, or both parts of MET need to be implemented. Abstract The receptor tyrosine kinase MET has gained attention as a therapeutic target. Although MET immunoreactivity is associated with progressive disease, use of targeted therapies has not yet led to major survival benefits. A possible explanation is the lack of companion diagnostics (CDx) that account for proteolytic processing. During presenilin-regulated intramembrane proteolysis, MET’s ectodomain is shed into the extracellular space, which is followed by γ-secretase-mediated cleavage of the residual membranous C-terminal fragment. The resulting intracellular fragment is degraded by the proteasome, leading to downregulation of MET signaling. Conversely, a membrane-bound MET fragment lacking the ectodomain (MET-EC-) can confer malignant potential. Use of C- and N-terminal MET monoclonal antibodies (moAbs) has illustrated that MET-EC- occurs in transmembranous C-terminal MET-positive oral squamous cell carcinoma (OSCC). Here, we propose that ectodomain shedding, resulting from G-protein-coupled receptor transactivation of epidermal growth factor receptor signaling, and/or overexpression of ADAM10/17 and/or MET, stabilizes and possibly activates MET-EC- in OSCC. As MET-EC- is associated with poor prognosis in OSCC, it potentially has impact on the use of targeted therapies. Therefore, MET-EC- should be incorporated in the design of CDx to improve patient stratification and ultimately prolong survival. Hence, MET-EC- requires further investigation seen its oncogenic and predictive properties.
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Affiliation(s)
- Maria J. De Herdt
- Department of Otorhinolaryngology and Head and Neck Surgery, Erasmus MC, Cancer Institute, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands; (B.v.d.S.); (R.J.B.d.J.); (J.A.H.)
- Correspondence: ; Tel.: +31-10-7044490
| | - Berdine van der Steen
- Department of Otorhinolaryngology and Head and Neck Surgery, Erasmus MC, Cancer Institute, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands; (B.v.d.S.); (R.J.B.d.J.); (J.A.H.)
| | - Robert J. Baatenburg de Jong
- Department of Otorhinolaryngology and Head and Neck Surgery, Erasmus MC, Cancer Institute, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands; (B.v.d.S.); (R.J.B.d.J.); (J.A.H.)
| | - Leendert H. J. Looijenga
- Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands;
- Department of Pathology, Erasmus MC, Cancer Institute, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands
| | - Senada Koljenović
- Department of Pathology, Antwerp University Hospital, 2650 Edegem, Belgium;
| | - Jose A. Hardillo
- Department of Otorhinolaryngology and Head and Neck Surgery, Erasmus MC, Cancer Institute, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands; (B.v.d.S.); (R.J.B.d.J.); (J.A.H.)
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17
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Design, Synthesis and Anticancer Profile of New 4-(1 H-benzo[ d]imidazol-1-yl)pyrimidin-2-amine-Linked Sulfonamide Derivatives with V600EBRAF Inhibitory Effect. Int J Mol Sci 2021; 22:ijms221910491. [PMID: 34638829 PMCID: PMC8508980 DOI: 10.3390/ijms221910491] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 09/18/2021] [Accepted: 09/22/2021] [Indexed: 01/07/2023] Open
Abstract
A new series of 4-(1H-benzo[d]imidazol-1-yl)pyrimidin-2-amine linked sulfonamide derivatives 12a–n was designed and synthesized according to the structure of well-established V600EBRAF inhibitors. The terminal sulfonamide moiety was linked to the pyrimidine ring via either ethylamine or propylamine bridge. The designed series was tested at fixed concentration (1 µM) against V600EBRAF, finding that 12e, 12i and 12l exhibited the strongest inhibitory activity among all target compounds and 12l had the lowest IC50 of 0.49 µM. They were further screened on NCI 60 cancer cell lines to reveal that 12e showed the most significant growth inhibition against multiple cancer cell lines. Therefore, cell cycle analysis of 12e was conducted to investigate the effect on cell cycle progression. Finally, virtual docking studies was performed to gain insights for the plausible binding modes of vemurafenib, 12i, 12e and 12l.
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18
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A Novel Monoclonal Antibody Targeting Cancer-Specific Plectin Has Potent Antitumor Activity in Ovarian Cancer. Cells 2021; 10:cells10092218. [PMID: 34571866 PMCID: PMC8466582 DOI: 10.3390/cells10092218] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 08/19/2021] [Accepted: 08/24/2021] [Indexed: 01/25/2023] Open
Abstract
Cancer-specific plectin (CSP) is a pro-tumorigenic protein selectively expressed on the cell surface of major cancers, including ovarian cancer (OC). Despite its assessable localization, abundance, and functional significance, the therapeutic efficacy of targeting CSP remains unexplored. Here, we generated and investigated the anticancer effects of a novel CSP-targeting monoclonal antibody, 1H11, in OC models. Its therapeutic efficacy as a monotherapy and in combination with chemotherapy was evaluated in vitro using two OC cell lines and in vivo by a subcutaneous ovarian cancer model. 1H11 demonstrated rapid internalization and high affinity and specificity for both human and murine CSP. Moreover, 1H11 induced significant and selective cytotoxicity (EC50 = 260 nM), G0/G1 arrest, and decreased OC cell migration. Mechanistically, these results are associated with increased ROS levels and reduced activation of the JAK2-STAT3 pathway. In vivo, 1H11 decreased Ki67 expression, induced 65% tumor growth inhibition, and resulted in 30% tumor necrosis. Moreover, 1H11 increased chemosensitivity to cisplatin resulting in 60% greater tumor growth inhibition compared to cisplatin alone. Taken together, CSP-targeting with 1H11 exhibits potent anticancer activity against ovarian cancer and is deserving of future clinical development.
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19
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Xu Y, Tian H, Luan CG, Sun K, Bao PJ, Zhang HY, Zhang N. Telocytes promote hepatocellular carcinoma by activating the ERK signaling pathway and miR-942-3p/MMP9 axis. Cell Death Discov 2021; 7:209. [PMID: 34376644 PMCID: PMC8355302 DOI: 10.1038/s41420-021-00592-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 06/09/2021] [Accepted: 07/19/2021] [Indexed: 12/21/2022] Open
Abstract
In China, hepatocellular carcinoma (HCC) is considered a malignant tumor with poor prognosis, frequent metastasis, and a high relapse rate. Telocytes (TCs) participate in tumorigenic, invasive, and migratory processes by secreting functional proteins and transmitting cell-to-cell information, but their functions in HCC are still unknown. TC counts and MMP9 expression in liver cancer tissues were measured using immunohistochemistry, western blotting, and RT-PCR. Primary TCs from liver para-cancer tissues were cultured in vitro. To verify the role of TCs in HCC, a metastatic cancer animal model was established using three types of liver cancer cell lines in vivo. TCs promoted HCC cell metastasis by MMP9 expression in vitro and in vivo. Platelet-derived growth factor-alpha (PDGF-α), secreted by HCC cells, activated the Ras/ERK signaling pathway in TCs, thereby increasing MMP9 expression; Moreover, miR-942-3p suppressed MMP9 expression in TCs. Our results reveal the role of TCs in HCC and the mechanisms by which they elicit their effects, and they may serve as novel prognostic markers for HCC.
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Affiliation(s)
- Ying Xu
- Shandong First Medical University and Shandong Academy of Medical Science, Shandong Cancer Hospital and Institute, Ji'nan, Shandong, China
| | - Hu Tian
- The First Affiliated Hospital of Shandong First Medical University, General Surgery, Ji'nan, Shandong, China.
| | - Chao Guang Luan
- Ji 'nan Municipal Three Hospitals, General Surgery, Ji'nan, Shandong, China
| | - Kai Sun
- The First Affiliated Hospital of Shandong First Medical University, General Surgery, Ji'nan, Shandong, China
| | - Peng Jin Bao
- Shandong First Medical University and Shandong Academy of Medical Science, Shandong Cancer Hospital and Institute, Ji'nan, Shandong, China
| | - Hua Yu Zhang
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Ji'nan, Shandong, China
| | - Nan Zhang
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Ji'nan, Shandong, China
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20
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Moreno V, Greil R, Yachnin J, Majem M, Wermke M, Arkenau HT, Basque JR, Nidamarthy PK, Kapoor S, Cui X, Giovannini M. Pharmacokinetics and safety of capmatinib with food in patients with MET-dysregulated advanced solid tumors. Clin Ther 2021; 43:1092-1111. [PMID: 34053700 DOI: 10.1016/j.clinthera.2021.04.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 04/06/2021] [Accepted: 04/11/2021] [Indexed: 10/21/2022]
Abstract
PURPOSE In the Phase II GEOMETRY mono-1 study, the potent and selective mesenchymal-epithelial transition (MET) inhibitor capmatinib exhibited considerable efficacy in MET exon 14 skipping (METex14)-mutated metastatic non-small cell lung cancer at a dose of 400 mg BID. The current recommended dose is 400 mg BID in tablet formulation, with or without food. This article reports the pharmacokinetic (PK) profile, safety, and tolerability of capmatinib 300 and 400 mg BID given with food in MET-dysregulated advanced solid tumors. METHODS This multicenter, open-label, Phase I study enrolled adult patients with MET-dysregulated advanced solid tumors. In the dose escalation phase, capmatinib tablets were orally administered at a dose of 300 mg BID with food; if tolerated, the dose escalation cohort of 400 mg BID was to be opened to enrollment. In the expansion phase, patients were to be enrolled at the higher of the tolerated doses. Tablets were taken within 30 minutes of an unrestricted meal type, except on cycle 1 day 1 (C1D1) and cycle 1 day 7 (C1D7), when they were given with a high-fat meal. The primary objectives were to determine the higher of the tolerated study doses and assess PK variables, with a secondary objective of safety. FINDINGS Overall, 35 patients (300 mg BID, n = 8; 400 mg BID, n = 27) with MET-dysregulated advanced solid tumors were enrolled; all patients had received prior antineoplastic therapy, and the most common primary site was lung (45.7%). Among PK-evaluable patients, the median Tmax for capmatinib after administration with a high-fat meal (on C1D1/C1D7) was 4.0 to 5.6 hours across doses. At steady state (C1D7), capmatinib accumulation was low across dose levels (geometric mean of accumulation ratios, 1.29-1.69), with an increase in exposure (AUCtau and Cmax) from 300 to 400 mg BID. There were no occurrences of dose-limiting toxicity. All patients experienced at least 1 adverse event, and treatment-related adverse events occurred in 28 patients (80%; 300 mg BID, n = 6; 400 mg BID, n = 22), the most frequent of which were fatigue (37.1%) and nausea (34.3%). IMPLICATIONS Capmatinib tablet formulation at a dose of up to 400 mg BID with food is well tolerated in patients with MET-dysregulated advanced solid tumors, with safety observations consistent with the existing profile under fasted conditions. These findings support the capmatinib dosing recommendation of 400 mg BID with or without food. ClinicalTrials.gov identifier: NCT02925104.
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Affiliation(s)
- Victor Moreno
- START Madrid-FJD, Hospital Fundación Jímenez Díaz, Madrid, Spain.
| | - Richard Greil
- IIIrd Medical Department, Paracelsus Medical University, Salzburg Cancer Research Institute, Salzburg, Austria
| | - Jeffrey Yachnin
- Department of Oncology-Pathology, Karolinska Institutet and University Hospital, Stockholm, Sweden
| | - Margarita Majem
- Medical Oncology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Martin Wermke
- Medical Clinic I, University Hospital Carl Gustav Carus, NCT/UCC Early Clinical Trial Unit, Dresden, Germany
| | - Hendrik-Tobias Arkenau
- Medical Oncology, Sarah Cannon Research Institute UK, London, United Kingdom; Cancer Institute, University College London, London, United Kingdom
| | | | | | - Shruti Kapoor
- Novartis Healthcare Private Limited, Hyderabad, India
| | - Xiaoming Cui
- Novartis Institutes for BioMedical Research, East Hanover, New Jersey
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21
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Integrated computational approaches on pyrazoline derivatives as B-Raf kinase inhibitors for the development of novel anticancer agents. J Mol Struct 2021. [DOI: 10.1016/j.molstruc.2020.129861] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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22
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Schmidt U, Heller G, Timelthaler G, Heffeter P, Somodi Z, Schweifer N, Sibilia M, Berger W, Csiszar A. The FAM3C locus that encodes interleukin-like EMT inducer (ILEI) is frequently co-amplified in MET-amplified cancers and contributes to invasiveness. J Exp Clin Cancer Res 2021; 40:69. [PMID: 33596971 PMCID: PMC7890988 DOI: 10.1186/s13046-021-01862-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 02/01/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Gene amplification of MET, which encodes for the receptor tyrosine kinase c-MET, occurs in a variety of human cancers. High c-MET levels often correlate with poor cancer prognosis. Interleukin-like EMT inducer (ILEI) is also overexpressed in many cancers and is associated with metastasis and poor survival. The gene for ILEI, FAM3C, is located close to MET on chromosome 7q31 in an amplification "hotspot", but it is unclear whether FAMC3 amplification contributes to elevated ILEI expression in cancer. In this study we have investigated FAMC3 copy number gain in different cancers and its potential connection to MET amplifications. METHODS FAMC3 and MET copy numbers were investigated in various cancer samples and 200 cancer cell lines. Copy numbers of the two genes were correlated with mRNA levels, with relapse-free survival in lung cancer patient samples as well as with clinicopathological parameters in primary samples from 49 advanced stage colorectal cancer patients. ILEI knock-down and c-MET inhibition effects on proliferation and invasiveness of five cancer cell lines and growth of xenograft tumors in mice were then investigated. RESULTS FAMC3 was amplified in strict association with MET amplification in several human cancers and cancer cell lines. Increased FAM3C and MET copy numbers were tightly linked and correlated with increased gene expression and poor survival in human lung cancer and with extramural invasion in colorectal carcinoma. Stable ILEI shRNA knock-down did not influence proliferation or sensitivity towards c-MET-inhibitor induced proliferation arrest in cancer cells, but impaired both c-MET-independent and -dependent cancer cell invasion. c-MET inhibition reduced ILEI secretion, and shRNA mediated ILEI knock-down prevented c-MET-signaling induced elevated expression and secretion of matrix metalloproteinase (MMP)-2 and MMP-9. Combination of ILEI knock-down and c-MET-inhibition significantly reduced the invasive outgrowth of NCI-H441 and NCI-H1993 lung tumor xenografts by inhibiting proliferation, MMP expression and E-cadherin membrane localization. CONCLUSIONS These novel findings suggest MET amplifications are often in reality MET-FAM3C co-amplifications with tight functional cooperation. Therefore, the clinical relevance of this frequent cancer amplification hotspot, so far dedicated purely to c-MET function, should be re-evaluated to include ILEI as a target in the therapy of c-MET-amplified human carcinomas.
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Affiliation(s)
- Ulrike Schmidt
- Research Institute of Molecular Pathology, Dr. Bohr-Gasse 3, A-1030 Vienna, Austria
| | - Gerwin Heller
- Department of Medicine I, Division of Oncology, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria
| | - Gerald Timelthaler
- Department of Medicine I, Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria
| | - Petra Heffeter
- Department of Medicine I, Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria
| | - Zsolt Somodi
- Department of Oncology, Bacs-Kiskun County Teaching Hospital, Kecskemet, Hungary
- Present Address: Parexel International, 2 Federal St, Billerica, MA USA
| | | | - Maria Sibilia
- Department of Medicine I, Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria
| | - Walter Berger
- Department of Medicine I, Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria
| | - Agnes Csiszar
- Department of Medicine I, Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria
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23
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Wang JQ, Teng QX, Lei ZN, Ji N, Cui Q, Fu H, Lin L, Yang DH, Fan YF, Chen ZS. Reversal of Cancer Multidrug Resistance (MDR) Mediated by ATP-Binding Cassette Transporter G2 (ABCG2) by AZ-628, a RAF Kinase Inhibitor. Front Cell Dev Biol 2020; 8:601400. [PMID: 33364237 PMCID: PMC7753047 DOI: 10.3389/fcell.2020.601400] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 09/30/2020] [Indexed: 12/13/2022] Open
Abstract
Overexpression of ABCG2 remains a major impediment to successful cancer treatment, because ABCG2 functions as an efflux pump of chemotherapeutic agents and causes clinical multidrug resistance (MDR). Therefore, it is important to uncover effective modulators to circumvent ABCG2-mediated MDR in cancers. In this study, we reported that AZ-628, a RAF kinase inhibitor, effectively antagonizes ABCG2-mediated MDR in vitro. Our results showed that AZ-628 completely reversed ABCG2-mediated MDR at a non-toxic concentration (3 μM) without affecting ABCB1-, ABCC1-, or ABCC10 mediated MDR. Further studies revealed that the reversal mechanism was by attenuating ABCG2-mediated efflux and increasing intracellular accumulation of ABCG2 substrate drugs. Moreover, AZ-628 stimulated ABCG2-associated ATPase activity in a concentration-dependent manner. Docking and molecular dynamics simulation analysis showed that AZ-628 binds to the same site as ABCG2 substrate drugs with higher score. Taken together, our studies indicate that AZ-628 could be used in combination chemotherapy against ABCG2-mediated MDR in cancers.
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Affiliation(s)
- Jing-Quan Wang
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States
| | - Qiu-Xu Teng
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States
| | - Zi-Ning Lei
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States
| | - Ning Ji
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States
| | - Qingbin Cui
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States.,School of Public Health, Guangzhou Medical University, Guangzhou, China
| | - Han Fu
- School of Public Health, Guangzhou Medical University, Guangzhou, China
| | - Lizhu Lin
- Cancer Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Dong-Hua Yang
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States
| | - Ying-Fang Fan
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States.,Department of Hepatobiliary Surgery I, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States
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24
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Joosten SPJ, Spaargaren M, Clevers H, Pals ST. Hepatocyte growth factor/MET and CD44 in colorectal cancer: partners in tumorigenesis and therapy resistance. Biochim Biophys Acta Rev Cancer 2020; 1874:188437. [PMID: 32976979 DOI: 10.1016/j.bbcan.2020.188437] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 09/09/2020] [Accepted: 09/09/2020] [Indexed: 12/12/2022]
Abstract
Intestinal epithelial self-renewal is a tightly controlled process, which is critically dependent on WNT signalling. Aberrant activation of the WNT pathway in intestinal stem cells (ISCs) results in constitutive transcription of target genes, which collectively drive malignant transformation in colorectal cancer (CRC). However, the contribution of individual genes to intestinal homeostasis and tumorigenesis often is incompletely defined. Here, we discuss converging evidence indicating that the receptor tyrosine kinase (RTK) MET and its ligand hepatocyte growth factor (HGF) play a major role in the intestinal damage response, as well as in intestinal tumorigenesis, by controlling the proliferation, survival, motility, and stemness of normal and neoplastic intestinal epithelial cells. These activities of MET are promoted by specific CD44 isoforms expressed by ISCs. The accrued data indicate that MET and the EGFR have overlapping roles in the biology of intestinal epithelium and that metastatic CRCs can exploit this redundancy to escape from EGFR-targeted treatments, co-opting HGF/MET/CD44v signalling. Hence, targeting both pathways may be required for effective treatment of (a subset of) CRCs. The RTK identity of MET, the distinctive 'plasminogen-like' structure and activation mode of its ligand HGF, and the specific collaboration of MET with CD44, provide several unique targeting options, which merit further exploration.
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Affiliation(s)
- Sander P J Joosten
- Department of Pathology and Cancer Center Amsterdam (CCA), Amsterdam University Medical Centers, Loc. AMC, the Netherlands
| | - Marcel Spaargaren
- Department of Pathology and Cancer Center Amsterdam (CCA), Amsterdam University Medical Centers, Loc. AMC, the Netherlands
| | - Hans Clevers
- Hubrecht Institute, University of Utrecht, Utrecht, the Netherlands
| | - Steven T Pals
- Department of Pathology and Cancer Center Amsterdam (CCA), Amsterdam University Medical Centers, Loc. AMC, the Netherlands..
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25
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Song Z, Xu C, He Y, Li F, Wang W, Zhu Y, Gao Y, Ji M, Chen M, Lai J, Cheng W, Benes CH, Chen L. Simultaneous Detection of Gene Fusions and Base Mutations in Cancer Tissue Biopsies by Sequencing Dual Nucleic Acid Templates in Unified Reaction. Clin Chem 2020; 66:178-187. [PMID: 31810998 DOI: 10.1373/clinchem.2019.308833] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Accepted: 10/07/2019] [Indexed: 01/23/2023]
Abstract
BACKGROUND Targeted next-generation sequencing is a powerful method to comprehensively identify biomarkers for cancer. Starting material is currently either DNA or RNA for different variations, but splitting to 2 assays is burdensome and sometimes unpractical, causing delay or complete lack of detection of critical events, in particular, potent and targetable fusion events. An assay that analyzes both templates in a streamlined process is eagerly needed. METHODS We developed a single-tube, dual-template assay and an integrated bioinformatics pipeline for relevant variant calling. RNA was used for fusion detection, whereas DNA was used for single-nucleotide variations (SNVs) and insertion and deletions (indels). The reaction chemistry featured barcoded adaptor ligation, multiplexed linear amplification, and multiplexed PCR for noise reduction and novel fusion detection. An auxiliary quality control assay was also developed. RESULTS In a 1000-sample lung tumor cohort, we identified all major SNV/indel hotspots and fusions, as well as MET exon 14 skipping and several novel or rare fusions. The occurrence frequencies were in line with previous reports and were verified by Sanger sequencing. One noteworthy fusion event was HLA-DRB1-MET that constituted the second intergenic MET fusion ever detected in lung cancer. CONCLUSIONS This method should benefit not only a majority of patients carrying core actionable targets but also those with rare variations. Future extension of this assay to RNA expression and DNA copy number profiling of target genes such as programmed death-ligand 1 may provide additional biomarkers for immune checkpoint therapies.
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Affiliation(s)
- Zhengbo Song
- Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang Province, PR China
| | - Chunwei Xu
- Department of Pathology, Fujian Cancer Hospital and Fujian Medical University, Fuzhou, Fujian Province, PR China
| | - Yunwei He
- HeliTec Biotechnologies, Shenzhen, Guangdong Province, PR China
| | - Fugui Li
- Cancer Research Institute of Zhongshan City, Zhongshan, Guangdong Province, PR China
| | - Wenxian Wang
- Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang Province, PR China
| | - Youcai Zhu
- Department of Thoracic Diagnosis and Treatment Center, Zhejiang Rongjun Hospital, Jiaxing, Zhejiang Province, PR China
| | - Yanqiu Gao
- HeliTec Biotechnologies, Shenzhen, Guangdong Province, PR China
| | - Mingfang Ji
- Cancer Research Institute of Zhongshan City, Zhongshan, Guangdong Province, PR China
| | - Miao Chen
- HeliTec Biotechnologies, Shenzhen, Guangdong Province, PR China
| | - Jiajia Lai
- HeliTec Biotechnologies, Shenzhen, Guangdong Province, PR China
| | - Weimin Cheng
- Cancer Research Institute of Zhongshan City, Zhongshan, Guangdong Province, PR China
| | - Cyril H Benes
- Massachusetts General Hospital Cancer Research Center and Harvard Medical School, Charlestown, MA
| | - Li Chen
- HeliTec Biotechnologies, Shenzhen, Guangdong Province, PR China
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26
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Abdel-Maksoud MS, Ali EM, Ammar UM, Mersal KI, Yoo KH, Oh CH. Design and synthesis of novel pyrrolo[2,3-b]pyridine derivatives targeting V600EBRAF. Bioorg Med Chem 2020; 28:115493. [DOI: 10.1016/j.bmc.2020.115493] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 04/04/2020] [Accepted: 04/05/2020] [Indexed: 02/06/2023]
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27
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Kang HN, Kim JH, Park AY, Choi JW, Lim SM, Kim J, Shin EJ, Hong MH, Pyo KH, Yun MR, Kim DH, Lee H, Yoon SO, Kim DH, Park YM, Byeon HK, Jung I, Paik S, Koh YW, Cho BC, Kim HR. Establishment and characterization of patient-derived xenografts as paraclinical models for head and neck cancer. BMC Cancer 2020; 20:316. [PMID: 32293356 PMCID: PMC7160896 DOI: 10.1186/s12885-020-06786-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 03/25/2020] [Indexed: 02/08/2023] Open
Abstract
Background We investigated whether head and neck squamous cell carcinoma (HNSCC) patient-derived xenografts (PDXs) reaffirm patient responses to anti-cancer therapeutics. Methods Tumors from HNSCC patients were transplanted into immunodeficient mice and propagated via subsequent implantation. We evaluated established PDXs by histology, genomic profiling, and in vivo anti-cancer efficacy testing to confirm them as the authentic in vivo platform. Results From 62 HNSCCs, 15 (24%) PDXs were established. The primary cancer types were tongue (8), oropharynx (3), hypopharynx (1), ethmoid sinus cancer (1), supraglottic cancer (1), and parotid gland (1); six PDXs (40%) were established from biopsy specimens from advanced HNSCC. PDXs mostly retained donor characteristics and remained stable across passages. PIK3CA (H1047R), HRAS (G12D), and TP53 mutations (H193R, I195T, R248W, R273H, E298X) and EGFR, CCND1, MYC, and PIK3CA amplifications were identified. Using the acquisition method, biopsy showed a significantly higher engraftment rate when compared with that of surgical resection (100% [6/6] vs. 16.1% [9/56], P < 0.001). Specimens obtained from metastatic sites showed a significantly higher engraftment rate than did those from primary sites (100% [9/9] vs. 11.3% [6/53], P < 0.001). Three PDX models from HPV-positive tumors were established, as compared to 12 from HPV-negative (15.8% [3/19] and 27.9% [12/43] respectively, P = 0.311), suggesting that HPV positivity tends to show a low engraftment rate. Drug responses in PDX recapitulated the clinical responses of the matching patients with pan-HER inhibitors and pan-PI3K inhibitor. Conclusions Genetically and clinically annotated HNSCC PDXs could be useful preclinical tools for evaluating biomarkers, therapeutic targets, and new drug discovery.
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Affiliation(s)
- Han Na Kang
- JE-UK Institute for Cancer Research, JEUK Co. Ltd., Gumi-City, Kyungbuk, South Korea
| | - Jae-Hwan Kim
- JE-UK Institute for Cancer Research, JEUK Co. Ltd., Gumi-City, Kyungbuk, South Korea
| | - A-Young Park
- JE-UK Institute for Cancer Research, JEUK Co. Ltd., Gumi-City, Kyungbuk, South Korea
| | - Jae Woo Choi
- JE-UK Institute for Cancer Research, JEUK Co. Ltd., Gumi-City, Kyungbuk, South Korea.,Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea
| | - Sun Min Lim
- Division of Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, Seongnam-si, South Korea
| | - Jinna Kim
- Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea
| | - Eun Joo Shin
- JE-UK Institute for Cancer Research, JEUK Co. Ltd., Gumi-City, Kyungbuk, South Korea
| | - Min Hee Hong
- Yonsei Cancer Center, Division of Medical Oncology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, South Korea
| | - Kyoung-Ho Pyo
- JE-UK Institute for Cancer Research, JEUK Co. Ltd., Gumi-City, Kyungbuk, South Korea.,Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea
| | - Mi Ran Yun
- JE-UK Institute for Cancer Research, JEUK Co. Ltd., Gumi-City, Kyungbuk, South Korea
| | - Dong Hwi Kim
- JE-UK Institute for Cancer Research, JEUK Co. Ltd., Gumi-City, Kyungbuk, South Korea
| | - Hanna Lee
- Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea
| | - Sun Och Yoon
- Department of Radiology, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Da Hee Kim
- Department of Otorhinolaryngology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, South Korea
| | - Young Min Park
- Department of Otorhinolaryngology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, South Korea
| | - Hyung Kwon Byeon
- Department of Otolaryngology-Head and Neck Surgery Korea, University College of Medicine, Seoul, South Korea
| | - Inkyung Jung
- Department of Biostatistics and Medical Informatics, Yonsei University College of Medicine, Seoul, South Korea
| | - Soonmyung Paik
- Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea
| | - Yoon Woo Koh
- Department of Otorhinolaryngology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, South Korea.
| | - Byoung Chul Cho
- JE-UK Institute for Cancer Research, JEUK Co. Ltd., Gumi-City, Kyungbuk, South Korea. .,Yonsei Cancer Center, Division of Medical Oncology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, South Korea.
| | - Hye Ryun Kim
- Yonsei Cancer Center, Division of Medical Oncology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, South Korea.
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Palve V, Liao Y, Remsing Rix LL, Rix U. Turning liabilities into opportunities: Off-target based drug repurposing in cancer. Semin Cancer Biol 2020; 68:209-229. [PMID: 32044472 DOI: 10.1016/j.semcancer.2020.02.003] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 01/29/2020] [Accepted: 02/03/2020] [Indexed: 12/12/2022]
Abstract
Targeted drugs and precision medicine have transformed the landscape of cancer therapy and significantly improved patient outcomes in many cases. However, as therapies are becoming more and more tailored to smaller patient populations and acquired resistance is limiting the duration of clinical responses, there is an ever increasing demand for new drugs, which is not easily met considering steadily rising drug attrition rates and development costs. Considering these challenges drug repurposing is an attractive complementary approach to traditional drug discovery that can satisfy some of these needs. This is facilitated by the fact that most targeted drugs, despite their implicit connotation, are not singularly specific, but rather display a wide spectrum of target selectivity. Importantly, some of the unintended drug "off-targets" are known anticancer targets in their own right. Others are becoming recognized as such in the process of elucidating off-target mechanisms that in fact are responsible for a drug's anticancer activity, thereby revealing potentially new cancer vulnerabilities. Harnessing such beneficial off-target effects can therefore lead to novel and promising precision medicine approaches. Here, we will discuss experimental and computational methods that are employed to specifically develop single target and network-based off-target repurposing strategies, for instance with drug combinations or polypharmacology drugs. By illustrating concrete examples that have led to clinical translation we will furthermore examine the various scientific and non-scientific factors that cumulatively determine the success of these efforts and thus can inform the future development of new and potentially lifesaving off-target based drug repurposing strategies for cancers that constitute important unmet medical needs.
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Affiliation(s)
- Vinayak Palve
- Department of Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA
| | - Yi Liao
- Department of Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA
| | - Lily L Remsing Rix
- Department of Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA
| | - Uwe Rix
- Department of Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA.
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29
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Mikhaylenko DS, Klimov AV, Matveev VB, Samoylova SI, Strelnikov VV, Zaletaev DV, Lubchenko LN, Alekseev BY, Nemtsova MV. Case of Hereditary Papillary Renal Cell Carcinoma Type I in a Patient With a Germline MET Mutation in Russia. Front Oncol 2020; 9:1566. [PMID: 32039030 PMCID: PMC6985093 DOI: 10.3389/fonc.2019.01566] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 12/24/2019] [Indexed: 12/24/2022] Open
Abstract
Hereditary papillary renal carcinoma (HPRC) is a rare autosomal dominant disease characterized by the development of multiple papillary type I renal cell carcinomas. This hereditary kidney cancer form is caused by activating mutations in MET. Descriptions of patients with HPRC are scarce in the world literature, and no cases have been described in open sources in Russia. Here, we describe a 28-year-old female Russian patient with 7 and 10 primary papillary renal cell carcinomas in the left and right kidneys, respectively. The patient did not have a family history of any of the known hereditary cancer syndromes. A comprehensive medical examination was performed in 2016 including computed tomography and pathomorphological analysis. The observed tumors were resected in a two-step surgical treatment. In February 2019, no sign of disease progression was detected in follow-up medical examination. Molecular genetic analysis revealed the germline heterozygous missense variant in MET: c.3328G>A (p.V1110I; CM990852). We have discussed the biological effects of the detected mutation and the utility of DNA diagnostics for treating patients with HPRC.
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Affiliation(s)
- Dmitry S Mikhaylenko
- Laboratory of Medical Genetics, Institute of Molecular Medicine, Scientific Biotechnological Park of Biomedicine, Sechenov University, Moscow, Russia.,Laboratory of Pathology and Molecular Genetics, N. Lopatkin Institute of Urology and Interventional Radiology - Branch of the National Medical Research Center of Radiology, Moscow, Russia.,Laboratory of Epigenetics, Research Centre for Medical Genetics Named After Academician N. P. Bochkov, Moscow, Russia
| | - Alexey V Klimov
- Department of Urology, Institute of Clinical Oncology, N. N. Blokhin National Medical Research Center of Oncology, Moscow, Russia
| | - Vsevolod B Matveev
- Department of Urology, Institute of Clinical Oncology, N. N. Blokhin National Medical Research Center of Oncology, Moscow, Russia
| | - Svetlana I Samoylova
- Laboratory of Medical Genetics, Institute of Molecular Medicine, Scientific Biotechnological Park of Biomedicine, Sechenov University, Moscow, Russia.,Laboratory of Pathology and Molecular Genetics, N. Lopatkin Institute of Urology and Interventional Radiology - Branch of the National Medical Research Center of Radiology, Moscow, Russia
| | - Vladimir V Strelnikov
- Laboratory of Epigenetics, Research Centre for Medical Genetics Named After Academician N. P. Bochkov, Moscow, Russia
| | - Dmitry V Zaletaev
- Laboratory of Medical Genetics, Institute of Molecular Medicine, Scientific Biotechnological Park of Biomedicine, Sechenov University, Moscow, Russia.,Laboratory of Epigenetics, Research Centre for Medical Genetics Named After Academician N. P. Bochkov, Moscow, Russia
| | - Ludmila N Lubchenko
- Department of Urology, Institute of Clinical Oncology, N. N. Blokhin National Medical Research Center of Oncology, Moscow, Russia
| | - Boris Y Alekseev
- Laboratory of Pathology and Molecular Genetics, N. Lopatkin Institute of Urology and Interventional Radiology - Branch of the National Medical Research Center of Radiology, Moscow, Russia
| | - Marina V Nemtsova
- Laboratory of Medical Genetics, Institute of Molecular Medicine, Scientific Biotechnological Park of Biomedicine, Sechenov University, Moscow, Russia.,Laboratory of Epigenetics, Research Centre for Medical Genetics Named After Academician N. P. Bochkov, Moscow, Russia
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Souza LDSD, Carrero Horta IP, de Souza Rosa L, Barbosa Lima LG, Santos da Rosa J, Montenegro J, da Silva Santos L, Nana de Castro RB, Freitas-Silva O, Teodoro AJ. Effect of the roasting levels of Coffea arabica L. extracts on their potential antioxidant capacity and antiproliferative activity in human prostate cancer cells. RSC Adv 2020; 10:30115-30126. [PMID: 35518253 PMCID: PMC9056273 DOI: 10.1039/d0ra01179g] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Accepted: 07/24/2020] [Indexed: 12/11/2022] Open
Abstract
Coffee, besides being one of the most consumed stimulating beverages in the world, has important bioactive activities, which have been attracting increasing attention from researchers. However, the standard process of roasting causes changes in its chemical composition. In the present study, extracts obtained from green and roasted beans (light, medium and dark) of Coffea arabica Linnaeus were submitted to high-power ultrasonic extraction and atomization by spray drying. Colorimetric analysis was used to classify the roasting levels of the dried extract samples. The effects of the roasting process on the bioactivity of the dried extracts were verified through the following assays: caffeine, chlorogenic acid and caffeic acid, by HPLC-PDA; total phenolics by Folin–Ciocalteu; antioxidant activity by DPPH, FRAP, ABTS and ORAC; antiproliferative activity, using the MTT assay; and cell cycle and apoptosis by flow cytometry in metastatic prostate cancer cell lines from bone (PC-3) and brain (DU-145). The results showed that the lowest levels of caffeine, chlorogenic and caffeic acids were observed in dark roasted coffee. In comparison to medium and dark extracts in PC-3 cells, the green and light coffee extracts had higher antioxidant activities and promoted cytotoxicity followed by cell cycle arrest in phase S and apoptosis induction. Thus, the roasting level of the coffee extracts may be related to the potential chemoprotective effects of Coffea arabica L. in prostate cancer cells. Coffee, besides being one of the most consumed stimulating beverages in the world, has important bioactive activities, which have been attracting increasing attention from researchers.![]()
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Affiliation(s)
| | | | - Lana de Souza Rosa
- Laboratory of Functional Foods
- Universidade Federal do Estado do Rio de Janeiro
- Rio de Janeiro
- Brazil
| | | | - Jeane Santos da Rosa
- Empresa Brasileira de Pesquisa Agropecuária
- Embrapa Agroindústria de Alimentos
- Rio de Janeiro
- Brazil
| | - Julia Montenegro
- Laboratory of Functional Foods
- Universidade Federal do Estado do Rio de Janeiro
- Rio de Janeiro
- Brazil
| | - Lauriza da Silva Santos
- Laboratory of Functional Foods
- Universidade Federal do Estado do Rio de Janeiro
- Rio de Janeiro
- Brazil
| | | | - Otniel Freitas-Silva
- Laboratory of Functional Foods
- Universidade Federal do Estado do Rio de Janeiro
- Rio de Janeiro
- Brazil
- Empresa Brasileira de Pesquisa Agropecuária
| | - Anderson Junger Teodoro
- Laboratory of Functional Foods
- Universidade Federal do Estado do Rio de Janeiro
- Rio de Janeiro
- Brazil
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31
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Abdel-Maksoud MS, Ammar UM, El-Gamal MI, Gamal El-Din MM, Mersal KI, Ali EM, Yoo KH, Lee KT, Oh CH. Design, synthesis, and anticancer activity of imidazo[2,1-b]oxazole-based RAF kinase inhibitors. Bioorg Chem 2019; 93:103349. [DOI: 10.1016/j.bioorg.2019.103349] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 07/27/2019] [Accepted: 10/05/2019] [Indexed: 10/25/2022]
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32
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Network-based Biased Tree Ensembles (NetBiTE) for Drug Sensitivity Prediction and Drug Sensitivity Biomarker Identification in Cancer. Sci Rep 2019; 9:15918. [PMID: 31685861 PMCID: PMC6828742 DOI: 10.1038/s41598-019-52093-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 10/07/2019] [Indexed: 12/15/2022] Open
Abstract
We present the Network-based Biased Tree Ensembles (NetBiTE) method for drug sensitivity prediction and drug sensitivity biomarker identification in cancer using a combination of prior knowledge and gene expression data. Our devised method consists of a biased tree ensemble that is built according to a probabilistic bias weight distribution. The bias weight distribution is obtained from the assignment of high weights to the drug targets and propagating the assigned weights over a protein-protein interaction network such as STRING. The propagation of weights, defines neighborhoods of influence around the drug targets and as such simulates the spread of perturbations within the cell, following drug administration. Using a synthetic dataset, we showcase how application of biased tree ensembles (BiTE) results in significant accuracy gains at a much lower computational cost compared to the unbiased random forests (RF) algorithm. We then apply NetBiTE to the Genomics of Drug Sensitivity in Cancer (GDSC) dataset and demonstrate that NetBiTE outperforms RF in predicting IC50 drug sensitivity, only for drugs that target membrane receptor pathways (MRPs): RTK, EGFR and IGFR signaling pathways. We propose based on the NetBiTE results, that for drugs that inhibit MRPs, the expression of target genes prior to drug administration is a biomarker for IC50 drug sensitivity following drug administration. We further verify and reinforce this proposition through control studies on, PI3K/MTOR signaling pathway inhibitors, a drug category that does not target MRPs, and through assignment of dummy targets to MRP inhibiting drugs and investigating the variation in NetBiTE accuracy.
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Palechor-Ceron N, Krawczyk E, Dakic A, Simic V, Yuan H, Blancato J, Wang W, Hubbard F, Zheng YL, Dan H, Strome S, Cullen K, Davidson B, Deeken JF, Choudhury S, Ahn PH, Agarwal S, Zhou X, Schlegel R, Furth PA, Pan CX, Liu X. Conditional Reprogramming for Patient-Derived Cancer Models and Next-Generation Living Biobanks. Cells 2019; 8:E1327. [PMID: 31717887 PMCID: PMC6912808 DOI: 10.3390/cells8111327] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 10/14/2019] [Accepted: 10/25/2019] [Indexed: 12/21/2022] Open
Abstract
Traditional cancer models including cell lines and animal models have limited applications in both basic and clinical cancer research. Genomics-based precision oncology only help 2-20% patients with solid cancer. Functional diagnostics and patient-derived cancer models are needed for precision cancer biology. In this review, we will summarize applications of conditional cell reprogramming (CR) in cancer research and next generation living biobanks (NGLB). Together with organoids, CR has been cited in two NCI (National Cancer Institute, USA) programs (PDMR: patient-derived cancer model repository; HCMI: human cancer model initiatives. HCMI will be distributed through ATCC). Briefly, the CR method is a simple co-culture technology with a Rho kinase inhibitor, Y-27632, in combination with fibroblast feeder cells, which allows us to rapidly expand both normal and malignant epithelial cells from diverse anatomic sites and mammalian species and does not require transfection with exogenous viral or cellular genes. Establishment of CR cells from both normal and tumor tissue is highly efficient. The robust nature of the technique is exemplified by the ability to produce 2 × 106 cells in five days from a core biopsy of tumor tissue. Normal CR cell cultures retain a normal karyotype and differentiation potential and CR cells derived from tumors retain their tumorigenic phenotype. CR also allows us to enrich cancer cells from urine (for bladder cancer), blood (for prostate cancer), and pleural effusion (for non-small cell lung carcinoma). The ability to produce inexhaustible cell populations using CR technology from small biopsies and cryopreserved specimens has the potential to transform biobanking repositories (NGLB: next-generation living biobank) and current pathology practice by enabling genetic, biochemical, metabolomic, proteomic, and biological assays, including chemosensitivity testing as a functional diagnostics tool for precision cancer medicine. We discussed analyses of patient-derived matched normal and tumor models using a case with tongue squamous cell carcinoma as an example. Last, we summarized applications in cancer research, disease modeling, drug discovery, and regenerative medicine of CR-based NGLB.
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Affiliation(s)
- Nancy Palechor-Ceron
- Department of Pathology, Center for Cell Reprogramming, Georgetown University Medical Center, Washington, DC 20057, USA; (N.P.-C.); (E.K.); (A.D.); (V.S.); (H.Y.); (S.C.); (S.A.); (R.S.)
| | - Ewa Krawczyk
- Department of Pathology, Center for Cell Reprogramming, Georgetown University Medical Center, Washington, DC 20057, USA; (N.P.-C.); (E.K.); (A.D.); (V.S.); (H.Y.); (S.C.); (S.A.); (R.S.)
| | - Aleksandra Dakic
- Department of Pathology, Center for Cell Reprogramming, Georgetown University Medical Center, Washington, DC 20057, USA; (N.P.-C.); (E.K.); (A.D.); (V.S.); (H.Y.); (S.C.); (S.A.); (R.S.)
| | - Vera Simic
- Department of Pathology, Center for Cell Reprogramming, Georgetown University Medical Center, Washington, DC 20057, USA; (N.P.-C.); (E.K.); (A.D.); (V.S.); (H.Y.); (S.C.); (S.A.); (R.S.)
| | - Hang Yuan
- Department of Pathology, Center for Cell Reprogramming, Georgetown University Medical Center, Washington, DC 20057, USA; (N.P.-C.); (E.K.); (A.D.); (V.S.); (H.Y.); (S.C.); (S.A.); (R.S.)
| | - Jan Blancato
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA; (J.B.); (W.W.); (Y.-L.Z.); (P.A.F.)
| | - Weisheng Wang
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA; (J.B.); (W.W.); (Y.-L.Z.); (P.A.F.)
| | - Fleesie Hubbard
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland, Baltimore, MD 21201, USA; (F.H.); (H.D.); (S.S.); (K.C.)
| | - Yun-Ling Zheng
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA; (J.B.); (W.W.); (Y.-L.Z.); (P.A.F.)
| | - Hancai Dan
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland, Baltimore, MD 21201, USA; (F.H.); (H.D.); (S.S.); (K.C.)
| | - Scott Strome
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland, Baltimore, MD 21201, USA; (F.H.); (H.D.); (S.S.); (K.C.)
| | - Kevin Cullen
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland, Baltimore, MD 21201, USA; (F.H.); (H.D.); (S.S.); (K.C.)
| | - Bruce Davidson
- Department of Otorhinolaryngology-Head and Neck Surgery, Georgetown University Medical Center, Washington, DC 20057, USA;
| | - John F. Deeken
- Inova Translational Medicine Institute, Inova Health System, Fairfax, VA 22031, USA;
| | - Sujata Choudhury
- Department of Pathology, Center for Cell Reprogramming, Georgetown University Medical Center, Washington, DC 20057, USA; (N.P.-C.); (E.K.); (A.D.); (V.S.); (H.Y.); (S.C.); (S.A.); (R.S.)
| | - Peter H. Ahn
- Department of Radiation Medicine, Georgetown University Medical Center, Washington, DC 20057, USA;
| | - Seema Agarwal
- Department of Pathology, Center for Cell Reprogramming, Georgetown University Medical Center, Washington, DC 20057, USA; (N.P.-C.); (E.K.); (A.D.); (V.S.); (H.Y.); (S.C.); (S.A.); (R.S.)
| | - Xuexun Zhou
- iCryobiol and iFuture Technologies, Shanghai 200127, China;
| | - Richard Schlegel
- Department of Pathology, Center for Cell Reprogramming, Georgetown University Medical Center, Washington, DC 20057, USA; (N.P.-C.); (E.K.); (A.D.); (V.S.); (H.Y.); (S.C.); (S.A.); (R.S.)
| | - Priscilla A. Furth
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA; (J.B.); (W.W.); (Y.-L.Z.); (P.A.F.)
| | - Chong-Xian Pan
- University of California at Davis, Sacramento, CA 95817, USA;
| | - Xuefeng Liu
- Department of Pathology, Center for Cell Reprogramming, Georgetown University Medical Center, Washington, DC 20057, USA; (N.P.-C.); (E.K.); (A.D.); (V.S.); (H.Y.); (S.C.); (S.A.); (R.S.)
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA; (J.B.); (W.W.); (Y.-L.Z.); (P.A.F.)
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Mondal AM, Ma AH, Li G, Krawczyk E, Yuan R, Lu J, Schlegel R, Stamatakis L, Kowalczyk KJ, Philips GK, Pan CX, Liu X. Fidelity of a PDX-CR model for bladder cancer. Biochem Biophys Res Commun 2019; 517:49-56. [PMID: 31303270 DOI: 10.1016/j.bbrc.2019.06.165] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Accepted: 06/30/2019] [Indexed: 01/14/2023]
Abstract
Patient-derived xenografts (PDXs) are widely recognised as a more physiologically relevant preclinical model than standard cell lines, but are expensive and low throughput, have low engraftment rate and take a long time to develop. Our newly developed conditional reprogramming (CR) technology addresses many PDX drawbacks, but lacks many in vivo factors. Here we determined whether PDXs and CRCs of the same cancer origin maintain the biological fidelity and complement each for translational research and drug development. Four CRC lines were generated from bladder cancer PDXs. Short tandem repeat (STR) analyses revealed that CRCs and their corresponding parental PDXs shared the same STRs, suggesting common cancer origins. CRCs and their corresponding parental PDXs contained the same genetic alterations. Importantly, CRCs retained the same drug sensitivity with the corresponding downstream signalling activity as their corresponding parental PDXs. This suggests that CRCs and PDXs can complement each other, and that CRCs can be used for in vitro fast, high throughput and low cost screening while PDXs can be used for in vivo validation and study of the in vivo factors during translational research and drug development.
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Affiliation(s)
- Abdul M Mondal
- Center for Cell Reprograming, Department of Pathology, Georgetown University Medical Center, Washington DC, USA
| | - Ai-Hong Ma
- Division of Hematology and Oncology, Department of Internal Medicine, School of Medicine, University of California Davis, Washington DC, USA
| | - Guangzhao Li
- Center for Cell Reprograming, Department of Pathology, Georgetown University Medical Center, Washington DC, USA
| | - Ewa Krawczyk
- Center for Cell Reprograming, Department of Pathology, Georgetown University Medical Center, Washington DC, USA
| | - Ruan Yuan
- Division of Hematology and Oncology, Department of Internal Medicine, School of Medicine, University of California Davis, Washington DC, USA; Department of Urology, Renmin Hospital, Wuhan University, Washington DC, USA
| | - Jie Lu
- Center for Cell Reprograming, Department of Pathology, Georgetown University Medical Center, Washington DC, USA
| | - Richard Schlegel
- Center for Cell Reprograming, Department of Pathology, Georgetown University Medical Center, Washington DC, USA
| | - Lambros Stamatakis
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, USA; Department of Urology, MedStar Washington Hospital Center, Washington DC, USA
| | - Keith J Kowalczyk
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, USA; Department of Urology, MedStar Georgetown Hospital, Washington DC, USA
| | - George K Philips
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, USA; Department of Oncology, MedStar Georgetown Hospital, Washington DC, USA
| | - Chong-Xian Pan
- Division of Hematology and Oncology, Department of Internal Medicine, School of Medicine, University of California Davis, Washington DC, USA; VA Northern California Health Care System, Mather, CA, USA.
| | - Xuefeng Liu
- Center for Cell Reprograming, Department of Pathology, Georgetown University Medical Center, Washington DC, USA; Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, USA.
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Dutil J, Chen Z, Monteiro AN, Teer JK, Eschrich SA. An Interactive Resource to Probe Genetic Diversity and Estimated Ancestry in Cancer Cell Lines. Cancer Res 2019; 79:1263-1273. [PMID: 30894373 DOI: 10.1158/0008-5472.can-18-2747] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 11/08/2018] [Accepted: 12/26/2018] [Indexed: 12/21/2022]
Abstract
Recent work points to a lack of diversity in genomics studies from genome-wide association studies to somatic (tumor) genome analyses. Yet, population-specific genetic variation has been shown to contribute to health disparities in cancer risk and outcomes. Immortalized cancer cell lines are widely used in cancer research, from mechanistic studies to drug screening. Larger collections of cancer cell lines better represent the genomic heterogeneity found in primary tumors. Yet, the genetic ancestral origin of cancer cell lines is rarely acknowledged and often unknown. Using genome-wide genotyping data from 1,393 cancer cell lines from the Catalogue of Somatic Mutations in Cancer (COSMIC) and Cancer Cell Line Encyclopedia (CCLE), we estimated the genetic ancestral origin for each cell line. Our data indicate that cancer cell line collections are not representative of the diverse ancestry and admixture characterizing human populations. We discuss the implications of genetic ancestry and diversity of cellular models for cancer research and present an interactive tool, Estimated Cell Line Ancestry (ECLA), where ancestry can be visualized with reference populations of the 1000 Genomes Project. Cancer researchers can use this resource to identify cell line models for their studies by taking ancestral origins into consideration.
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Affiliation(s)
- Julie Dutil
- Cancer Biology Division, Ponce Research Institute, Ponce Health Sciences University, Ponce, Puerto Rico.
| | - Zhihua Chen
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Alvaro N Monteiro
- Cancer Epidemiology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Jamie K Teer
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Steven A Eschrich
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
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Garcia C, Buffet C, El Khattabi L, Rizk-Rabin M, Perlemoine K, Ragazzon B, Bertherat J, Cormier F, Groussin L. MET overexpression and activation favors invasiveness in a model of anaplastic thyroid cancer. Oncotarget 2019; 10:2320-2334. [PMID: 31040922 PMCID: PMC6481343 DOI: 10.18632/oncotarget.26798] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Accepted: 03/04/2019] [Indexed: 11/25/2022] Open
Abstract
In thyroid cancers, MET receptor overexpression has been associated with higher risk of metastatic progression. In this study, it was shown that the anaplastic thyroid cancer (ATC)-derived TTA1 cell line overexpressed MET. By using FISH and relative quantification by qPCR, it was demonstrated that this overexpression resulted from a MET amplification with more than 20 copies. As expected, MET overexpression led to its constitutive activation and upregulated signaling towards the MAPK, PI3K/AKT, STAT3 and NF-κB pathways. Since the usual feature of MET-amplified cell lines is the "MET addiction" for their cell proliferation, the effect of the highly selective ATP competitive MET inhibitor PHA665752 was analyzed. While PHA665752 strongly inhibited the MAPK pathway, it did not reduce cell proliferation in TTA1 cells (IC50 = 4100 nM). This resistance to PHA665752 of the TTA1 cell line was demonstrated to be related to EGFR-MET functional cross-talk and PI3K/AKT and NF-κB signaling. Nevertheless, PHA665752 suppressed the anchorage-independent growth capacity of the TTA1 cell line and reduced cell migration and invasion in a transwell assay. The role of activated MET in these neoplastic properties of the TTA1 cells was also proved with si-MET-RNA targeting. Thus, this work highlights the TTA1 cell line as the first model of MET amplification in an ATC cell line, which leads to MET constitutive activation and underlies its neoplastic properties. Besides being a useful model for MET inhibitors screening, the TTA1 cell line also supports the argument for searching for MET amplification in ATC, as it could have therapeutic implications.
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Affiliation(s)
- Cyril Garcia
- INSERM Unité 1016, Institut Cochin, Paris, France.,Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Institut Cochin, Paris, France.,Université Paris Descartes, Sorbonne Paris Cité, Paris, France.,Hôpital d'Instruction des Armées BEGIN, Saint-Mandé, France
| | - Camille Buffet
- INSERM Unité 1016, Institut Cochin, Paris, France.,Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Institut Cochin, Paris, France.,Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Laila El Khattabi
- INSERM Unité 1016, Institut Cochin, Paris, France.,Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Institut Cochin, Paris, France.,Université Paris Descartes, Sorbonne Paris Cité, Paris, France.,Cytogenetics Laboratory, APHP, Cochin Hospital, Paris, France
| | - Marthe Rizk-Rabin
- INSERM Unité 1016, Institut Cochin, Paris, France.,Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Institut Cochin, Paris, France.,Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Karine Perlemoine
- INSERM Unité 1016, Institut Cochin, Paris, France.,Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Institut Cochin, Paris, France.,Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Bruno Ragazzon
- INSERM Unité 1016, Institut Cochin, Paris, France.,Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Institut Cochin, Paris, France.,Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Jérôme Bertherat
- INSERM Unité 1016, Institut Cochin, Paris, France.,Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Institut Cochin, Paris, France.,Université Paris Descartes, Sorbonne Paris Cité, Paris, France.,Department of Endocrinology, APHP, Cochin Hospital, Paris, France
| | - Françoise Cormier
- INSERM Unité 1016, Institut Cochin, Paris, France.,Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Institut Cochin, Paris, France.,Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Lionel Groussin
- INSERM Unité 1016, Institut Cochin, Paris, France.,Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Institut Cochin, Paris, France.,Université Paris Descartes, Sorbonne Paris Cité, Paris, France.,Department of Endocrinology, APHP, Cochin Hospital, Paris, France
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Zou J, Zhu W, Meng H, Luo P, Zhang J. Efficacy and safety of selective internal radiotherapy versus sorafenib for intermediate-locally advanced hepatocellular carcinoma: a systematic review and meta-analysis. Expert Rev Gastroenterol Hepatol 2019; 13:271-279. [PMID: 30791765 DOI: 10.1080/17474124.2019.1570135] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Sorafenib (SOR) is recommended for locally advanced and metastatic hepatocellular carcinoma (HCC), but the tolerability of SOR is unsatisfactory. Selective internal radiotherapy (SIRT) has shown efficacy in intermediate-locally advanced HCC patients. This meta-analysis aimed to compare the efficacy and safety of SIRT and SOR in the treatment of intermediate-locally advanced HCC. METHODS We systematically searched the PubMed, Embase, Cochrane Library and Web of Science databases for eligible studies. The endpoints evaluated included the overall survival (OS), disease control rate (DCR), objective response rate (ORR) and grade≥3 adverse events (AEs). RESULTS Six studies were included in this analysis. The OS was similar between the two groups (HR 1.06, 95%CI 0.93-1.20; P = 0.40). There was no difference in the DCR between the two groups (RR 1.13, 95%CI 0.87-1.46; P = 0.35). However, the ORR in the SIRT group was significantly higher than that in the SOR group (RR 4.10, 95%CI 1.92-8.76; P = 0.0003). The incidence rate of grade≥3 AEs was higher in the SOR group. CONCLUSIONS In patients with intermediate-locally advanced HCC, SIRT and SOR result in similar survival rates. The improved toxicity profile of SIRT may help when choosing between the two treatments.
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Affiliation(s)
- Jingwen Zou
- a Oncology Center , Zhujiang Hospital of Southern Medical University , Guangzhou , Guangdong Province , China
| | - Weiliang Zhu
- a Oncology Center , Zhujiang Hospital of Southern Medical University , Guangzhou , Guangdong Province , China
| | - Hui Meng
- a Oncology Center , Zhujiang Hospital of Southern Medical University , Guangzhou , Guangdong Province , China
| | - Peng Luo
- a Oncology Center , Zhujiang Hospital of Southern Medical University , Guangzhou , Guangdong Province , China
| | - Jian Zhang
- a Oncology Center , Zhujiang Hospital of Southern Medical University , Guangzhou , Guangdong Province , China
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38
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Orlando E, Aebersold DM, Medová M, Zimmer Y. Oncogene addiction as a foundation of targeted cancer therapy: The paradigm of the MET receptor tyrosine kinase. Cancer Lett 2019; 443:189-202. [DOI: 10.1016/j.canlet.2018.12.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 11/20/2018] [Accepted: 12/03/2018] [Indexed: 12/13/2022]
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Wang X, Sun Z, Zimmermann MT, Bugrim A, Kocher JP. Predict drug sensitivity of cancer cells with pathway activity inference. BMC Med Genomics 2019; 12:15. [PMID: 30704449 PMCID: PMC6357358 DOI: 10.1186/s12920-018-0449-4] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Background Predicting cellular responses to drugs has been a major challenge for personalized drug therapy regimen. Recent pharmacogenomic studies measured the sensitivities of heterogeneous cell lines to numerous drugs, and provided valuable data resources to develop and validate computational approaches for the prediction of drug responses. Most of current approaches predict drug sensitivity by building prediction models with individual genes, which suffer from low reproducibility due to biologic variability and difficulty to interpret biological relevance of novel gene-drug associations. As an alternative, pathway activity scores derived from gene expression could predict drug response of cancer cells. Method In this study, pathway-based prediction models were built with four approaches inferring pathway activity in unsupervised manner, including competitive scoring approaches (DiffRank and GSVA) and self-contained scoring approaches (PLAGE and Z-score). These unsupervised pathway activity inference approaches were applied to predict drug responses of cancer cells using data from Cancer Cell Line Encyclopedia (CCLE). Results Our analysis on all the 24 drugs from CCLE demonstrated that pathway-based models achieved better predictions for 14 out of the 24 drugs, while taking fewer features as inputs. Further investigation on indicated that pathway-based models indeed captured pathways involving drug-related genes (targets, transporters and metabolic enzymes) for majority of drugs, whereas gene-models failed to identify these drug-related genes, in most cases. Among the four approaches, competitive scoring (DiffRank and GSVA) provided more accurate predictions and captured more pathways involving drug-related genes than self-contained scoring (PLAGE and Z-Score). Detailed interpretation of top pathways from the top method (DiffRank) highlights the merit of pathway-based approaches to predict drug response by identifying pathways relevant to drug mechanisms. Conclusion Taken together, pathway-based modeling with inferred pathway activity is a promising alternative to predict drug response, with the ability to easily interpret results and provide biological insights into the mechanisms of drug actions. Electronic supplementary material The online version of this article (10.1186/s12920-018-0449-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Xuewei Wang
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Zhifu Sun
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Michael T Zimmermann
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.,Present address: Bioinformatics Research and Development Laboratory, Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI, USA
| | | | - Jean-Pierre Kocher
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
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40
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Baltschukat S, Engstler BS, Huang A, Hao HX, Tam A, Wang HQ, Liang J, DiMare MT, Bhang HEC, Wang Y, Furet P, Sellers WR, Hofmann F, Schoepfer J, Tiedt R. Capmatinib (INC280) Is Active Against Models of Non–Small Cell Lung Cancer and Other Cancer Types with Defined Mechanisms of MET Activation. Clin Cancer Res 2019; 25:3164-3175. [DOI: 10.1158/1078-0432.ccr-18-2814] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 12/12/2018] [Accepted: 01/18/2019] [Indexed: 11/16/2022]
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Namekawa T, Ikeda K, Horie-Inoue K, Inoue S. Application of Prostate Cancer Models for Preclinical Study: Advantages and Limitations of Cell Lines, Patient-Derived Xenografts, and Three-Dimensional Culture of Patient-Derived Cells. Cells 2019; 8:cells8010074. [PMID: 30669516 PMCID: PMC6357050 DOI: 10.3390/cells8010074] [Citation(s) in RCA: 118] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2018] [Revised: 01/17/2019] [Accepted: 01/18/2019] [Indexed: 12/13/2022] Open
Abstract
Various preclinical models have been developed to clarify the pathophysiology of prostate cancer (PCa). Traditional PCa cell lines from clinical metastatic lesions, as exemplified by DU-145, PC-3, and LNCaP cells, are useful tools to define mechanisms underlying tumorigenesis and drug resistance. Cell line-based experiments, however, have limitations for preclinical studies because those cells are basically adapted to 2-dimensional monolayer culture conditions, in which the majority of primary PCa cells cannot survive. Recent tissue engineering enables generation of PCa patient-derived xenografts (PDXs) from both primary and metastatic lesions. Compared with fresh PCa tissue transplantation in athymic mice, co-injection of PCa tissues with extracellular matrix in highly immunodeficient mice has remarkably improved the success rate of PDX generation. PDX models have advantages to appropriately recapitulate the molecular diversity, cellular heterogeneity, and histology of original patient tumors. In contrast to PDX models, patient-derived organoid and spheroid PCa models in 3-dimensional culture are more feasible tools for in vitro studies for retaining the characteristics of patient tumors. In this article, we review PCa preclinical model cell lines and their sublines, PDXs, and patient-derived organoid and spheroid models. These PCa models will be applied to the development of new strategies for cancer precision medicine.
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Affiliation(s)
- Takeshi Namekawa
- Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Saitama 350-1241, Japan.
- Department of Urology, Graduate School of Medicine, Chiba University, Chiba, Chiba 260-8677, Japan.
| | - Kazuhiro Ikeda
- Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Saitama 350-1241, Japan.
| | - Kuniko Horie-Inoue
- Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Saitama 350-1241, Japan.
| | - Satoshi Inoue
- Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Saitama 350-1241, Japan.
- Department of Functional Biogerontology, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo 173-0015, Japan.
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Virzì AR, Gentile A, Benvenuti S, Comoglio PM. Reviving oncogenic addiction to MET bypassed by BRAF (G469A) mutation. Proc Natl Acad Sci U S A 2018; 115:10058-10063. [PMID: 30224486 PMCID: PMC6176587 DOI: 10.1073/pnas.1721147115] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Cancer clonal evolution is based on accrual of driving genetic alterations that are expected to cooperate and progressively increase malignancy. Little is known on whether any genetic alteration can hinder the oncogenic function of a coexisting alteration, so that therapeutic targeting of the one can, paradoxically, revive the function of the other. We report the case of a driver oncogene (MET) that is not only bypassed, but also disabled by the mutation of a downstream transducer (BRAF), and reignited by inhibition of the latter. In a metastasis originated from a cancer of unknown primary (CUP), the MET oncogene was amplified eightfold, but unexpectedly, the kinase was dephosphorylated and inactive. As result, specific drugs targeting MET (JNJ-38877605) failed to inhibit growth of xenografts derived from the patient. In addition to MET amplification, the patient harbored, as sole proliferative driver, a mutation hyperactivating BRAF (G469A). Surprisingly, specific blockade of the BRAF pathway was equally ineffective, and it was accompanied by rephosphorylation of the amplified MET oncoprotein and by revived addiction to MET. Mechanistically, MET inactivation in the context of the BRAF-activating mutation is driven through a negative feedback loop involving inactivation of PP2A phosphatase, which in turn leads to phosphorylation on MET inhibitory Ser985. Disruption of this feedback loop allows PP2A reactivation, removing the inhibitory phosphorylation from Ser985 and thereby unleashing MET kinase activity. Evidence is provided for a mechanism of therapeutic resistance to single-oncoprotein targeting, based on reactivation of a genetic alteration functionally dormant in targeted cancer cells.
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Affiliation(s)
- Anna Rita Virzì
- Laboratory of Molecular Therapeutics and Exploratory Research, Candiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia- Istituto di Ricovero e Cura a Carattere Scientifico (FPO-IRCCS), 10060 Candiolo, Italy
| | - Alessandra Gentile
- Laboratory of Molecular Therapeutics and Exploratory Research, Candiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia- Istituto di Ricovero e Cura a Carattere Scientifico (FPO-IRCCS), 10060 Candiolo, Italy
| | - Silvia Benvenuti
- Laboratory of Molecular Therapeutics and Exploratory Research, Candiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia- Istituto di Ricovero e Cura a Carattere Scientifico (FPO-IRCCS), 10060 Candiolo, Italy
| | - Paolo M Comoglio
- Laboratory of Molecular Therapeutics and Exploratory Research, Candiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia- Istituto di Ricovero e Cura a Carattere Scientifico (FPO-IRCCS), 10060 Candiolo, Italy
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Cell-Based Methods for Determination of Efficacy for Candidate Therapeutics in the Clinical Management of Cancer. Diseases 2018; 6:diseases6040085. [PMID: 30249005 PMCID: PMC6313784 DOI: 10.3390/diseases6040085] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 09/12/2018] [Accepted: 09/20/2018] [Indexed: 12/11/2022] Open
Abstract
Determination of therapeutic efficacy is a major challenge in developing treatment options for cancer. Prior to in vivo studies, candidate therapeutics are evaluated using cell-based in vitro methods to assess their anti-cancer potential. This review describes the utility and limitations of evaluating therapeutic efficacy using human tumor-derived cell lines. Indicators for therapeutic efficacy using tumor-derived cell lines include cell viability, cell proliferation, colony formation, cytotoxicity, cytostasis, induction of apoptosis, and cell cycle arrest. Cell panel screens, 3D tumor spheroid models, drug-drug/drug-radiation combinatorial analysis, and invasion/migration assays reveal analogous in vitro information. In animal models, cellular assays can assess tumor micro-environment and therapeutic delivery. The utility of tumor-derived cell lines for efficacy determination is manifest in numerous commercially approved drugs that have been applied in clinical management of cancer. Studies reveal most tumor-derived cell lines preserve the genomic signature of the primary tumor source and cell line-based data is highly predictive of subsequent clinical studies. However, cell-based data often disregards natural system components, resulting in cell autonomous outcomes. While 3D cell culture platforms can counter such limitations, they require additional time and cost. Despite the limitations, cell-based methods remain essential in early stages of anti-cancer drug development.
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44
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Van Nyen T, Moiola CP, Colas E, Annibali D, Amant F. Modeling Endometrial Cancer: Past, Present, and Future. Int J Mol Sci 2018; 19:E2348. [PMID: 30096949 PMCID: PMC6121384 DOI: 10.3390/ijms19082348] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Revised: 07/31/2018] [Accepted: 08/03/2018] [Indexed: 12/13/2022] Open
Abstract
Endometrial cancer is the most common type of cancer of the female reproductive tract. Although prognosis is generally good for patients with low-grade and early-stage diseases, the outcomes for high-grade and metastatic/recurrent cases remain poor, since traditional chemotherapy regimens based on platinum and taxanes have limited effects. No targeted agents have been approved so far, although several new drugs have been tested without striking results in clinical trials. Over the last decades, many efforts have been made towards the establishment and development of preclinical models, aiming at recapitulating the structural and molecular determinants of the disease. Here, we present an overview of the most commonly used in vitro and in vivo models and discuss their peculiar features, describing their main applications and the value in the advancement of both fundamental and translational endometrial cancer research.
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Affiliation(s)
- Tom Van Nyen
- Department of Oncology, Gynecological Oncology, KU Leuven, 3000 Leuven, Belgium.
| | - Cristian P Moiola
- Pathological Oncology Group, Biomedical Research Institute of Lleida (IRBLLEIDA), University Hospital Arnau de Vilanova, 25198 Lleida, Spain.
- Biomedical Research Group in Gynecology, Vall Hebron Institute of Research, CIBERONC, 08035 Barcelona, Spain.
| | - Eva Colas
- Biomedical Research Group in Gynecology, Vall Hebron Institute of Research, CIBERONC, 08035 Barcelona, Spain.
| | - Daniela Annibali
- Department of Oncology, Gynecological Oncology, KU Leuven, 3000 Leuven, Belgium.
| | - Frédéric Amant
- Department of Oncology, Gynecological Oncology, KU Leuven, 3000 Leuven, Belgium.
- Centre for Gynecologic Oncology Amsterdam (CGOA), Antoni Van Leeuwenhoek-Netherlands Cancer Institute (Avl-NKI) and University Medical Centra (UMC), 1066 CX Amsterdam, The Netherlands.
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45
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Deep analysis of acquired resistance to FGFR1 inhibitor identifies MET and AKT activation and an expansion of AKT1 mutant cells. Oncotarget 2018; 9:31549-31558. [PMID: 30140389 PMCID: PMC6101141 DOI: 10.18632/oncotarget.25862] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Accepted: 07/16/2018] [Indexed: 11/25/2022] Open
Abstract
The development of acquired resistance (AR) to tyrosine kinase inhibitors (TKIs) of FGFR1 activation is currently not well understood. To gain a deeper insight into this matter in lung cancer, we used the FGFR1-amplified DMS114 cell line and generated multiple clones with AR to an FGFR1-TKI. We molecularly scrutinized the resistant cells, using whole-exome sequencing, RNA sequencing and global DNA methylation analysis. Our results show a de novo activation of AKT and ERK, and a reactivation of mTOR. Furthermore, the resistant cells exhibited strong upregulation and activation of MET, indicating crosstalk between the FGFR1 and MET axes. The resistant cells also underwent a global decrease in promoter hypermethylation of the CpG islands. Finally, we observed clonal expansion of a pre-existing change in AKT1, leading to S266L substitution, within the kinase domain of AKT. Our results demonstrate that AR to FGFR1-TKI involves deep molecular changes that promote the activation of MET and AKT, coupled with common gene expression and DNA methylation profiles. The expansion of a substitution at AKT1 was the only shared genetic change, and this may have contributed to the AR.
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46
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Duan W, Liu Y. Targeted and synergistic therapy for hepatocellular carcinoma: monosaccharide modified lipid nanoparticles for the co-delivery of doxorubicin and sorafenib. DRUG DESIGN DEVELOPMENT AND THERAPY 2018; 12:2149-2161. [PMID: 30034219 PMCID: PMC6047861 DOI: 10.2147/dddt.s166402] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Purpose Targeted hepatocellular carcinoma therapy was carried out to improve the efficacy of liver cancer treatment. The purpose of this study was to design an N-acetylgalactosamine (NAcGal) modified and pH sensitive doxorubicin (DOX) prodrug (NAcGal-DOX) for the construction of lipid nanoparticles (LNPs). Methods NAcGal-DOX and sorafenib (SOR) co-loaded LNPs were designed and the synergistic effects were evaluated on human hepatic carcinoma (HepG2) cells in vitro and anti-hepatic carcinoma mice model in vivo. Results Cellular uptake efficiency of NAcGal modified LNPs was significantly higher than unmodified LNPs. NAcGal modified LNPs showed the most significant inhibition effect among all the samples tested. The results revealed that the LNPs system achieved significant synergistic effects, best tumor inhibition ability and the lowest systemic toxicity. Conclusion These results proved that the NAcGal conjugated and pH sensitive co-delivery nano-system could be a promising strategy for treatment of hepatocellular carcinoma.
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Affiliation(s)
- Wendu Duan
- Department of Hepatobiliary Surgery, Affiliated Hospital of Hebei University, Baoding, Hebei Province 071000, People's Republic of China,
| | - Yan Liu
- Department of Hepatobiliary Surgery, Affiliated Hospital of Hebei University, Baoding, Hebei Province 071000, People's Republic of China,
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47
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Hauser K, Negron C, Albanese SK, Ray S, Steinbrecher T, Abel R, Chodera JD, Wang L. Predicting resistance of clinical Abl mutations to targeted kinase inhibitors using alchemical free-energy calculations. Commun Biol 2018; 1:70. [PMID: 30159405 PMCID: PMC6110136 DOI: 10.1038/s42003-018-0075-x] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 05/15/2018] [Indexed: 12/13/2022] Open
Abstract
The therapeutic effect of targeted kinase inhibitors can be significantly reduced by intrinsic or acquired resistance mutations that modulate the affinity of the drug for the kinase. In cancer, the majority of missense mutations are rare, making it difficult to predict their impact on inhibitor affinity. This complicates the practice of precision medicine, pairing of patients with clinical trials, and development of next-generation inhibitors. Here, we examine the potential for alchemical free-energy calculations to predict how kinase mutations modulate inhibitor affinities to Abl, a major target in chronic myelogenous leukemia (CML). We find these calculations can achieve useful accuracy in predicting resistance for a set of eight FDA-approved kinase inhibitors across 144 clinically-identified point mutations, achieving a root mean square error in binding free energy changes of 1.1 0.9 1.3 kcal/mol (95% confidence interval) and correctly classifying mutations as resistant or susceptible with 88 82 93 % accuracy. Since these calculations are fast on modern GPUs, this benchmark establishes the potential for physical modeling to collaboratively support the rapid assessment and anticipation of the potential for patient mutations to affect drug potency in clinical applications.
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Affiliation(s)
| | | | - Steven K Albanese
- Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
- Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | | | | | | | - John D Chodera
- Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
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48
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Lee H, Kim N, Yoo YJ, Kim H, Jeong E, Choi S, Moon SU, Oh SH, Mills GB, Yoon S, Kim WY. β-catenin/TCF activity regulates IGF-1R tyrosine kinase inhibitor sensitivity in colon cancer. Oncogene 2018; 37:5466-5475. [PMID: 29895971 DOI: 10.1038/s41388-018-0362-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Revised: 05/06/2018] [Accepted: 05/25/2018] [Indexed: 12/19/2022]
Abstract
The availability of large-scale drug screening data on cell line panels provides a unique opportunity to identify predictive biomarkers for targeted drug efficacy. Analysis of diverse drug data on ~990 cancer cell lines revealed enhanced sensitivity of insulin-like growth factor 1 receptor/ Insulin Receptor (IGF-1R/IR) tyrosine kinase inhibitors (TKIs) in colon cancer cells. Interestingly, β-catenin/TCF(T cell factor)-responsive promoter activity exhibited a significant positive association with IGF-1R/IR TKI response, while the mutational status of direct upstream genes, such as CTNNB1 and APC, was not significantly associated with the response. The β-catenin/TCF activity high cell lines express components of IGF-1R/IR signaling more than the low cell lines explaining their enhanced sensitivity against IGF-1R/IR TKI. Reinforcing β-catenin/TCF responsive promoter activity by introducing CTNNB1 gain-of-function mutations into IGF-1R/IR TKI-resistant cells increased the expression and activity of IGF-1R/IR signaling components and also sensitized the cells to IGF-1R/IR TKIs in vitro and in vivo. Analysis of TCGA data revealed that the stronger β-catenin/TCF responsive promoter activity was associated with higher IGF-1R and IGF2 transcription in human colon cancer specimens as well. Collectively, compared to the mutational status of upstream genes, β-catenin/TCF responsive promoter activity has potential to be a stronger predictive positive biomarker for IGF-1R/IR TKI responses in colon cancer cells. The present study highlights the potential of transcriptional activity as therapeutic biomarkers for targeted therapies, overcoming the limited ability of upstream genetic mutations to predict responses.
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Affiliation(s)
- Hani Lee
- Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, 04310, Republic of Korea.,Center for Advanced Bioinformatics & Systems Medicine, Sookmyung Women's University, Seoul, 04310, Republic of Korea
| | - Nayoung Kim
- Center for Advanced Bioinformatics & Systems Medicine, Sookmyung Women's University, Seoul, 04310, Republic of Korea.,Department of Biological Sciences, Sookmyung Women's University, Seoul, 04310, Republic of Korea
| | - Young Ji Yoo
- Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, 04310, Republic of Korea.,Center for Advanced Bioinformatics & Systems Medicine, Sookmyung Women's University, Seoul, 04310, Republic of Korea
| | - Hyejin Kim
- Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, 04310, Republic of Korea.,Center for Advanced Bioinformatics & Systems Medicine, Sookmyung Women's University, Seoul, 04310, Republic of Korea
| | - Euna Jeong
- Center for Advanced Bioinformatics & Systems Medicine, Sookmyung Women's University, Seoul, 04310, Republic of Korea
| | - SeokGyeong Choi
- Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, 04310, Republic of Korea.,Center for Advanced Bioinformatics & Systems Medicine, Sookmyung Women's University, Seoul, 04310, Republic of Korea
| | - Sung Un Moon
- Center for Advanced Bioinformatics & Systems Medicine, Sookmyung Women's University, Seoul, 04310, Republic of Korea
| | - Seung Hyun Oh
- College of Pharmacy, Gachon University, Incheon, 21936, Republic of Korea
| | - Gordon B Mills
- Systems Biology, MD Anderson Cancer Center, University of Texas, Houston, TX, 77030, USA
| | - Sukjoon Yoon
- Center for Advanced Bioinformatics & Systems Medicine, Sookmyung Women's University, Seoul, 04310, Republic of Korea. .,Department of Biological Sciences, Sookmyung Women's University, Seoul, 04310, Republic of Korea.
| | - Woo-Young Kim
- Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, 04310, Republic of Korea. .,Center for Advanced Bioinformatics & Systems Medicine, Sookmyung Women's University, Seoul, 04310, Republic of Korea.
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49
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Comoglio PM, Trusolino L, Boccaccio C. Known and novel roles of the MET oncogene in cancer: a coherent approach to targeted therapy. Nat Rev Cancer 2018; 18:341-358. [PMID: 29674709 DOI: 10.1038/s41568-018-0002-y] [Citation(s) in RCA: 245] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The MET oncogene encodes an unconventional receptor tyrosine kinase with pleiotropic functions: it initiates and sustains neoplastic transformation when genetically altered ('oncogene addiction') and fosters cancer cell survival and tumour dissemination when transcriptionally activated in the context of an adaptive response to adverse microenvironmental conditions ('oncogene expedience'). Moreover, MET is an intrinsic modulator of the self-renewal and clonogenic ability of cancer stem cells ('oncogene inherence'). Here, we provide the latest findings on MET function in cancer by focusing on newly identified genetic abnormalities in tumour cells and recently described non-mutational MET activities in stromal cells and cancer stem cells. We discuss how MET drives cancer clonal evolution and progression towards metastasis, both ab initio and under therapeutic pressure. We then elaborate on the use of MET inhibitors in the clinic with a critical appraisal of failures and successes. Ultimately, we advocate a rationale to improve the outcome of anti-MET therapies on the basis of thorough consideration of the entire spectrum of MET-mediated biological responses, which implicates adequate patient stratification, meaningful biomarkers and appropriate clinical end points.
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Affiliation(s)
- Paolo M Comoglio
- Exploratory Research and Molecular Cancer Therapy, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.
| | - Livio Trusolino
- Translational Cancer Medicine, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
- Department of Oncology, University of Torino Medical School, Candiolo, Italy
| | - Carla Boccaccio
- Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
- Department of Oncology, University of Torino Medical School, Candiolo, Italy
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50
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Lee J, Geiss GK, Demirkan G, Vellano CP, Filanoski B, Lu Y, Ju Z, Yu S, Guo H, Bogatzki LY, Carter W, Meredith RK, Krishnamurthy S, Ding Z, Beechem JM, Mills GB. Implementation of a Multiplex and Quantitative Proteomics Platform for Assessing Protein Lysates Using DNA-Barcoded Antibodies. Mol Cell Proteomics 2018; 17:1245-1258. [PMID: 29531020 PMCID: PMC5986246 DOI: 10.1074/mcp.ra117.000291] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Revised: 02/17/2018] [Indexed: 11/06/2022] Open
Abstract
Molecular analysis of tumors forms the basis for personalized cancer medicine and increasingly guides patient selection for targeted therapy. Future opportunities for personalized medicine are highlighted by the measurement of protein expression levels via immunohistochemistry, protein arrays, and other approaches; however, sample type, sample quantity, batch effects, and "time to result" are limiting factors for clinical application. Here, we present a development pipeline for a novel multiplexed DNA-labeled antibody platform which digitally quantifies protein expression from lysate samples. We implemented a rigorous validation process for each antibody and show that the platform is amenable to multiple protocols covering nitrocellulose and plate-based methods. Results are highly reproducible across technical and biological replicates, and there are no observed "batch effects" which are common for most multiplex molecular assays. Tests from basal and perturbed cancer cell lines indicate that this platform is comparable to orthogonal proteomic assays such as Reverse-Phase Protein Array, and applicable to measuring the pharmacodynamic effects of clinically-relevant cancer therapeutics. Furthermore, we demonstrate the potential clinical utility of the platform with protein profiling from breast cancer patient samples to identify molecular subtypes. Together, these findings highlight the potential of this platform for enhancing our understanding of cancer biology in a clinical translation setting.
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Affiliation(s)
- Jinho Lee
- From the ‡The University of Texas M.D. Anderson Cancer Center, Department of Systems Biology, 1300 Moursund St., Houston, Texas 77030;
| | - Gary K Geiss
- §NanoString Technologies, Inc., 530 Fairview Ave N., Seattle, Washington 98109;
| | - Gokhan Demirkan
- §NanoString Technologies, Inc., 530 Fairview Ave N., Seattle, Washington 98109
| | - Christopher P Vellano
- From the ‡The University of Texas M.D. Anderson Cancer Center, Department of Systems Biology, 1300 Moursund St., Houston, Texas 77030
| | - Brian Filanoski
- §NanoString Technologies, Inc., 530 Fairview Ave N., Seattle, Washington 98109
| | - Yiling Lu
- From the ‡The University of Texas M.D. Anderson Cancer Center, Department of Systems Biology, 1300 Moursund St., Houston, Texas 77030
| | - Zhenlin Ju
- ¶The University of Texas M.D. Anderson Cancer Center, Department of Pathology, 1515 Holcombe Blvd, Houston, Texas 77030
| | - Shuangxing Yu
- From the ‡The University of Texas M.D. Anderson Cancer Center, Department of Systems Biology, 1300 Moursund St., Houston, Texas 77030
| | - Huifang Guo
- From the ‡The University of Texas M.D. Anderson Cancer Center, Department of Systems Biology, 1300 Moursund St., Houston, Texas 77030
| | - Lisa Y Bogatzki
- §NanoString Technologies, Inc., 530 Fairview Ave N., Seattle, Washington 98109
| | - Warren Carter
- §NanoString Technologies, Inc., 530 Fairview Ave N., Seattle, Washington 98109
| | - Rhonda K Meredith
- §NanoString Technologies, Inc., 530 Fairview Ave N., Seattle, Washington 98109
| | - Savitri Krishnamurthy
- ¶The University of Texas M.D. Anderson Cancer Center, Department of Pathology, 1515 Holcombe Blvd, Houston, Texas 77030
| | - Zhiyong Ding
- From the ‡The University of Texas M.D. Anderson Cancer Center, Department of Systems Biology, 1300 Moursund St., Houston, Texas 77030
| | - Joseph M Beechem
- §NanoString Technologies, Inc., 530 Fairview Ave N., Seattle, Washington 98109
| | - Gordon B Mills
- From the ‡The University of Texas M.D. Anderson Cancer Center, Department of Systems Biology, 1300 Moursund St., Houston, Texas 77030;
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