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Torres-Ayuso P, Brognard J. Defeating kinases that promote tumorigenesis through non-catalytic functions with PROTACs - PIM kinase as an example. Expert Opin Ther Targets 2025; 29:189-191. [PMID: 40304362 DOI: 10.1080/14728222.2025.2500418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Revised: 03/24/2025] [Accepted: 04/17/2025] [Indexed: 05/02/2025]
Affiliation(s)
- Pedro Torres-Ayuso
- Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
- Cancer Signaling and Microenvironment Program, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - John Brognard
- Laboratory of Cell and Developmental Signaling, National Cancer Institute, National Institutes of Health, Frederick, MD, USA
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2
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Wang D, Wang L, Zhang W, Xu K, Chen L, Guo Z, Wu K, Huang D, Zhao Y, Yao M, Zheng L, Ye C, Ran J, Zhou W, Liu X, Xu J. Extracellular vesicle-mediated gene therapy targets BRAF V600E-mutant colorectal cancer by inhibiting the MEK1/2-ERK1/2 pathway. J Nanobiotechnology 2025; 23:129. [PMID: 39979881 PMCID: PMC11843959 DOI: 10.1186/s12951-025-03205-4] [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: 10/23/2024] [Accepted: 02/05/2025] [Indexed: 02/22/2025] Open
Abstract
BACKGROUND Patients with colorectal cancer (CRC) harboring BRAF mutation have a poor prognosis. The median survival time for patients with advanced BRAFV600E-mutant CRC is only approximately one year. Owing to the insensitivity to standard chemotherapy, there are still no effective and highly specific treatment strategies available in clinical practice for CRC patients with BRAF mutation. Therefore, targeting the BRAFV600E mutation site, researching and exploring novel targeted therapies are essential to improve the survival rate of patients with this CRC subtype. AIM This study aims to develop a precise therapeutic system for BRAFV600E CRC, based on the carrier properties of extracellular vesicles (EVs) and gene therapy targeting BRAFV600E. METHOD We first obtained engineered cells capable of stably producing EVs loaded with BRAFV600E nucleic acid drugs (siBRAFV600E). Next, BRAFV600E-mutant and wild-type CRC cell lines, as well as corresponding subcutaneous and metastasis models, were used to evaluate the therapeutic efficacy of EVs-siBRAFV600E and explored the mechanism. Notably, patient-derived xenograft (PDX) models, which share the same molecular characteristics, pathological features, and heterogeneity as patients do, were utilized to further explore the therapeutic efficacy and mechanisms. RESULT EVs-siBRAFV600E specifically inhibited BRAFV600E CRC but didn't affect BRAF wild-type CRC in vitro and vivo. EVs-siBRAFV600E exerts its therapeutic effect by regulating the MEK1/2-ERK1/2 pathway, and it has demonstrated excellent therapeutic efficacy in PDX models. CONCLUSION The therapeutic EVs we constructed are effective and specific for the BRAFV600E-mutant CRC. This study provides a novel strategy for the treatment of CRC patients with BRAFV600E mutation.
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Affiliation(s)
- Di Wang
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
| | - Liwei Wang
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
| | - Wei Zhang
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, PR China
| | - Kaicheng Xu
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
| | - Liang Chen
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
| | - Ziye Guo
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
| | - Kaile Wu
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
| | - Donghua Huang
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
| | - Yubin Zhao
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
| | - Minjun Yao
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
| | - Liming Zheng
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
| | - Chenyi Ye
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
| | - Jisheng Ran
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China
| | - Wei Zhou
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, PR China.
| | - Xin Liu
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, PR China.
| | - Jianbin Xu
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, PR China.
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, 310009, PR China.
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China.
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, PR China.
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Chen L, Pruteanu-Malinici I, Dastur A, Yin X, Frederick D, Sadreyev RI, Benes CH. Transposon mediated functional genomic screening for BRAF inhibitor resistance reveals convergent Hippo and MAPK pathway activation events. Sci Rep 2025; 15:3048. [PMID: 39856157 PMCID: PMC11760944 DOI: 10.1038/s41598-025-86694-5] [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: 10/23/2024] [Accepted: 01/13/2025] [Indexed: 01/27/2025] Open
Abstract
Genotype-informed anticancer therapies such as BRAF inhibitors can show remarkable clinical efficacy in BRAF-mutant melanoma; however, drug resistance poses a major hurdle to successful cancer treatment. Many resistance events to targeted therapies have been identified, suggesting a complex path to improve therapeutics. Here, we showed the utility of a piggyBac transposon activation mutagenesis screen for the efficient identification of genes that are resistant to BRAF inhibition in melanoma. Although several forward genetic screens performed in the same context have identified a broad range of resistance genes that poorly overlap, an integrative analysis revealed a much smaller functional diversity of resistance mechanisms, including reactivation of the MAPK pathway, PI3K-AKT pathway, and Hippo pathway, suggesting that a relatively small number of therapeutic strategies might overcome resistance manifested by a large gene set. Moreover, we illustrated the pivotal role of the Hippo pathway effector TAZ (encoded by the WWTR1 gene) in mediating BRAF inhibition resistance through transcriptional regulation of receptor tyrosine kinases and through interactions with the E3 ubiquitin ligase NEDD4L.
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Affiliation(s)
- Li Chen
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, 02129, USA.
| | - Iulian Pruteanu-Malinici
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, 02129, USA
- Flagship Pioneering, Cambridge, MA, USA
| | - Anahita Dastur
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, 02129, USA
- Sonata Therapeutics, Watertown, MA, USA
| | - Xunqin Yin
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, 02129, USA
- Broad Institute, Cambridge, MA, USA
| | - Dennie Frederick
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, 02129, USA
- Broad Institute, Cambridge, MA, USA
| | - Ruslan I Sadreyev
- Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Cyril H Benes
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, 02129, USA
- Treeline Biosciences, San Diego, CA, USA
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Inoue H, Kuroda JI, Fujioka Y, Hata N, Mizoguchi M, Yoshii D, Sueyoshi H, Takeshima Y, Fujimoto K, Shinojima N, Sunami K, Mikami Y, Nakamura H, Mukasa A. Drug-resistant BRAF V600E-mutant recurrent pleomorphic xanthoastrocytoma, CNS WHO Grade 3 successfully resolved with incidental discontinuation of combined BRAF and MEK inhibitor therapy. Surg Neurol Int 2024; 15:417. [PMID: 39640311 PMCID: PMC11618650 DOI: 10.25259/sni_734_2024] [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: 08/28/2024] [Accepted: 10/10/2024] [Indexed: 12/07/2024] Open
Abstract
Background Combination therapy with BRAF and MEK inhibitor holds promise for treating gliomas harboring the BRAF V600E mutation; however, the development of acquired resistance remains a challenge. Case Description We describe a case of repeated recurrent BRAF-mutant pleomorphic xanthoastrocytoma (central nervous system World Health Organization grade 3) treated with combination therapy with BRAF and MEK inhibitor. The patient received dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor); however, she developed resistance to the combination therapy. Remarkably, incidental drug discontinuation contributed to the disappearance of the resistant tumor. The same phenomenon was repeatedly observed after that. Genetic analysis demonstrated that the resistant tumor had BRAF V600E amplification; the resistant tumor remained BRAF→MEK→ERK pathway dependent, and drug resistance might be due to elevated BRAF V600E expression. We speculated that ERK1/2 signal extremes caused by the discontinuation of the combination therapy affected the resistant tumor survival. Conclusion This case study provides important insights into novel treatment strategies and their underlying mechanisms for gliomas with BRAF mutations.
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Affiliation(s)
- Hirotaka Inoue
- Department of Neurosurgery, Kumamoto University Hospital, Kumamoto, Japan
| | - Jun-Ichiro Kuroda
- Department of Neurosurgery, Kumamoto University Hospital, Kumamoto, Japan
| | - Yutaka Fujioka
- Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Nobuhiro Hata
- Department of Neurosurgery, Oita University Faculty of Medicine, Yufu, Japan
| | | | - Daiki Yoshii
- Department of Diagnostic Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Hiroyuki Sueyoshi
- Department of Neurosurgery, Kumamoto University Hospital, Kumamoto, Japan
| | - Yuki Takeshima
- Department of Neurosurgery, Kumamoto University Hospital, Kumamoto, Japan
| | - Kenji Fujimoto
- Department of Neurosurgery, Kumamoto University Hospital, Kumamoto, Japan
| | - Naoki Shinojima
- Department of Neurosurgery, Kumamoto University Hospital, Kumamoto, Japan
| | - Kuniko Sunami
- Department of Laboratory Medicine, National Cancer Center Hospital, Chuo-ku, Japan
| | - Yoshiki Mikami
- Department of Diagnostic Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Hideo Nakamura
- Department of Neurosurgery, Kurume University School of Medicine, Kurume, Japan
| | - Akitake Mukasa
- Department of Neurosurgery, Kumamoto University Hospital, Kumamoto, Japan
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5
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Kolathur KK, Nag R, Shenoy PV, Malik Y, Varanasi SM, Angom RS, Mukhopadhyay D. Molecular Susceptibility and Treatment Challenges in Melanoma. Cells 2024; 13:1383. [PMID: 39195270 PMCID: PMC11352263 DOI: 10.3390/cells13161383] [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: 07/21/2024] [Revised: 08/15/2024] [Accepted: 08/17/2024] [Indexed: 08/29/2024] Open
Abstract
Melanoma is the most aggressive subtype of cancer, with a higher propensity to spread compared to most solid tumors. The application of OMICS approaches has revolutionized the field of melanoma research by providing comprehensive insights into the molecular alterations and biological processes underlying melanoma development and progression. This review aims to offer an overview of melanoma biology, covering its transition from primary to malignant melanoma, as well as the key genes and pathways involved in the initiation and progression of this disease. Utilizing online databases, we extensively explored the general expression profile of genes, identified the most frequently altered genes and gene mutations, and examined genetic alterations responsible for drug resistance. Additionally, we studied the mechanisms responsible for immune checkpoint inhibitor resistance in melanoma.
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Affiliation(s)
- Kiran Kumar Kolathur
- Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical Sciences (MCOPS), Manipal Academy of Higher Education (MAHE), Manipal 576104, Karnataka, India;
| | - Radhakanta Nag
- Department of Microbiology, College of Basic Science & Humanities, Odisha University of Agriculture & Technology (OUAT), Bhubaneswar 751003, Odisha, India;
| | - Prathvi V Shenoy
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences (MCOPS), Manipal Academy of Higher Education (MAHE), Manipal 576104, Karnataka, India; (P.V.S.); (Y.M.)
| | - Yagya Malik
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences (MCOPS), Manipal Academy of Higher Education (MAHE), Manipal 576104, Karnataka, India; (P.V.S.); (Y.M.)
| | - Sai Manasa Varanasi
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, FL 32224, USA; (S.M.V.); (R.S.A.)
| | - Ramcharan Singh Angom
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, FL 32224, USA; (S.M.V.); (R.S.A.)
| | - Debabrata Mukhopadhyay
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, FL 32224, USA; (S.M.V.); (R.S.A.)
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Nishiyama A, Sato S, Sakaguchi H, Kotani H, Yamashita K, Ohtsubo K, Nanjo S, Yano S, Mizuguchi K, Ikeda H, Takeuchi S. Challenges in the treatment of BRAF K601E-mutated lung carcinoma: a case report of rapid response and resistance to dabrafenib and trametinib. Front Oncol 2024; 14:1374594. [PMID: 39040442 PMCID: PMC11260700 DOI: 10.3389/fonc.2024.1374594] [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: 01/22/2024] [Accepted: 06/26/2024] [Indexed: 07/24/2024] Open
Abstract
We report a case of limited effectiveness of dabrafenib and trametinib in a 59-year-old man with poorly differentiated lung carcinoma and a rare BRAF K601E mutation. The patient, unresponsive to chemotherapy and immunotherapy, received these targeted agents as second-line treatment. Despite a notable initial response, tumor regression lasted only 52 days. A subsequent liquid biopsy revealed additional alterations (BRAF amplification, KIT amplification, TP53 S241F), indicating a complex resistance mechanism. This case underscores the challenges in treating BRAF K601E-mutant lung carcinoma, emphasizing the need for advanced molecular diagnostics, personalized approaches, and further research into more effective therapies for unique genetic profiles.
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Affiliation(s)
- Akihiro Nishiyama
- Department of Medical Oncology, Kanazawa University Hospital, Kanazawa, Japan
| | - Shigeki Sato
- Department of Medical Oncology, Kanazawa University Hospital, Kanazawa, Japan
| | - Hiroyuki Sakaguchi
- Department of Medical Oncology, Kanazawa University Hospital, Kanazawa, Japan
| | - Hiroshi Kotani
- Department of Medical Oncology, Kanazawa University Hospital, Kanazawa, Japan
| | - Kaname Yamashita
- Department of Medical Oncology, Kanazawa University Hospital, Kanazawa, Japan
| | - Koushiro Ohtsubo
- Department of Medical Oncology, Kanazawa University Hospital, Kanazawa, Japan
| | - Shigeki Nanjo
- Department of Respiratory Medicine, Kanazawa University Hospital, Kanazawa, Japan
| | - Seiji Yano
- Department of Respiratory Medicine, Kanazawa University Hospital, Kanazawa, Japan
| | - Keishi Mizuguchi
- Department of Diagnostic Pathology, Kanazawa University Hospital, Kanazawa, Japan
| | - Hiroko Ikeda
- Department of Diagnostic Pathology, Kanazawa University Hospital, Kanazawa, Japan
| | - Shinji Takeuchi
- Department of Medical Oncology, Kanazawa University Hospital, Kanazawa, Japan
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Featherston T, Paumann-Page M, Hampton MB. Melanoma redox biology and the emergence of drug resistance. Adv Cancer Res 2024; 162:145-171. [PMID: 39069368 DOI: 10.1016/bs.acr.2024.06.004] [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] [Indexed: 07/30/2024]
Abstract
Melanoma is the deadliest form of skin cancer, with the loss of approximately 60,000 lives world-wide each year. Despite the development of targeted therapeutics, including compounds that have selectivity for mutant oncoproteins expressed only in cancer cells, many patients are either unresponsive to initial therapy or their tumors acquire resistance. This results in five-year survival rates of below 25%. New strategies that either kill drug-resistant melanoma cells or prevent their emergence would be extremely valuable. Melanoma, like other cancers, has long been described as being under increased oxidative stress, resulting in an increased reliance on antioxidant defense systems. Changes in redox homeostasis are most apparent during metastasis and during the metabolic reprogramming associated with the development of treatment resistance. This review discusses oxidative stress in melanoma, with a particular focus on targeting antioxidant pathways to limit the emergence of drug resistant cells.
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Affiliation(s)
- Therese Featherston
- Mātai Hāora-Centre for Redox Biology and Medicine, Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand
| | - Martina Paumann-Page
- Mātai Hāora-Centre for Redox Biology and Medicine, Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand.
| | - Mark B Hampton
- Mātai Hāora-Centre for Redox Biology and Medicine, Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand.
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8
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Zhai J, Liu H. Cross-Domain Feature Disentanglement for Interpretable Modeling of Tumor Microenvironment Impact on Drug Response. IEEE J Biomed Health Inform 2024; 28:4382-4392. [PMID: 38607708 DOI: 10.1109/jbhi.2024.3387930] [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: 04/14/2024]
Abstract
High-throughput screening technology has enabled the generation of large-scale drug responses across hundreds of cancer cell lines. There remains a significant gap between in vitro cell lines and actual tumors in vivo in terms of their response to drug treatments yet. This is because tumors consist of a complex cellular composition and histopathology structure, known as the tumor microenvironment (TME), which greatly impacts the drug cytotoxicity against tumor cells. To date, no study has focused on modeling the impact of the TME on clinical drug response. In this study, we postulated that the intricate complexity of an actual tumor can be conceptually simplified into two separable components: cancerous cells and the tumor microenvironment. This assumption allowed us to model the influence of these two constituent parts on drug response through feature disentanglement. We employed a domain adaptation network to decouple and extract features from tumor transcriptional profiles. Specifically, two denoising autoencoders were separately used to extract features from cell lines (source domain) and tumors (target domain) for partial domain alignment and feature decoupling. The private encoder was enforced to extract information only about the TME. Moreover, to ensure generalizability to novel drugs, we employed a graph attention network to learn the latent representation of drugs, enabling us to linearly model the drug perturbation on cellular state in latent space. We validated our model on a benchmark dataset and demonstrated its superior performance in predicting clinical drug response and dissecting the influence of the TME on drug efficacy.
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9
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Liu-Smith F, Lin J. Unsupervised Analysis Reveals the Involvement of Key Immune Response Genes and the Matrisome in Resistance to BRAF and MEK Inhibitors in Melanoma. Cancers (Basel) 2024; 16:2313. [PMID: 39001376 PMCID: PMC11240363 DOI: 10.3390/cancers16132313] [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: 06/12/2024] [Revised: 06/14/2024] [Accepted: 06/17/2024] [Indexed: 07/16/2024] Open
Abstract
Melanoma tumors exhibit a wide range of heterogeneity in genomics even with shared mutations in the MAPK pathway, including BRAF mutations. Consistently, adaptive drug resistance to BRAF inhibitors and/or BRAF plus MEK inhibitors also exhibits a wide range of heterogeneous responses, which poses an obstacle for discovering common genes and pathways that can be used in clinic for overcoming drug resistance. This study objectively analyzed two sets of previously published tumor genomics data comparing pre-treated melanoma tumors and BRAFi- and/or MEKi-resistant tumors. Heterogeneity in response to BRAFi and BRAFi/MEKi was evident because the pre-treated tumors and resistant tumors did not exhibit a tendency of clustering together. Differentially expressed gene (DEG) analysis revealed eight genes and two related enriched signature gene sets (matrisome and matrisome-associated signature gene sets) shared by both sets of data. The matrisome was closely related to the tumor microenvironment and immune response, and five out of the eight shared genes were also related to immune response. The PLXNC1 gene links the shared gene set and the enriched signature gene sets as it presented in all analysis results. As the PLXNC1 gene was up-regulated in the resistant tumors, we validated the up-regulation of this gene in a laboratory using vemurafenib-resistant cell lines. Given its role in promoting inflammation, this study suggests that resistant tumors exhibit an inflammatory tumor microenvironment. The involvement of the matrisome and the specific set of immune genes identified in this study may provide new opportunities for developing future therapeutic methods.
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Affiliation(s)
- Feng Liu-Smith
- Department of Preventive Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38105, USA;
- Department of Dermatology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38105, USA
| | - Jianjian Lin
- Department of Preventive Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38105, USA;
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10
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Beech C, Hechtman JF. Molecular Approach to Colorectal Carcinoma: Current Evidence and Clinical Application. Clin Lab Med 2024; 44:221-238. [PMID: 38821642 DOI: 10.1016/j.cll.2023.08.011] [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] [Indexed: 06/02/2024]
Abstract
Colorectal carcinoma is one of the most common cancer types in men and women, responsible for both the third highest incidence of new cancer cases and the third highest cause of cancer deaths. In the last several decades, the molecular mechanisms surrounding colorectal carcinoma's tumorigenesis have become clearer through research, providing new avenues for diagnostic testing and novel approaches to therapeutics. Laboratories are tasked with providing the most current information to help guide clinical decisions. In this review, we summarize the current knowledge surrounding colorectal carcinoma tumorigenesis and highlight clinically relevant molecular testing.
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Affiliation(s)
- Cameron Beech
- Department of Pathology, Yale New Haven Hospital, New Haven, CT, USA
| | - Jaclyn F Hechtman
- Molecular and GI Pathologist, NeoGenomics Laboratories, Fort Myers, FL, USA.
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11
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Alhamdan YR, Ayoub NM, Jaradat SK, Shatnawi A, Yaghan RJ. BRAF Expression and Copy Number Alterations Predict Unfavorable Tumor Features and Adverse Outcomes in Patients With Breast Cancer. Int J Breast Cancer 2024; 2024:6373900. [PMID: 38919805 PMCID: PMC11199069 DOI: 10.1155/2024/6373900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 04/15/2024] [Accepted: 05/07/2024] [Indexed: 06/27/2024] Open
Abstract
Background: The role of BRAF in breast cancer pathogenesis is still unclear. To address this knowledge gap, this study is aimed at evaluating the impact of BRAF gene expression and copy number alterations (CNAs) on clinicopathologic characteristics and survival in patients with breast cancer. Methods: The Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset was obtained from the cBioPortal public domain. Tumoral BRAF mRNA expression and CNAs along with demographic and tumor data for patients with breast cancer were retrieved. The association of BRAF expression and CNAs with breast cancer clinicopathologic characteristics was analyzed. The impact of BRAF mRNA expression on the overall survival of patients was assessed using Kaplan-Meier survival analysis. Results: BRAF gene mRNA log intensity expression was positively correlated with tumor size and the Nottingham Prognostic Index (NPI) (p < 0.001). Alternatively, BRAF gene expression was negatively correlated with the age at diagnosis (p = 0.003). The average BRAF mRNA expression was significantly higher in premenopausal patients, patients with high tumor grade, hormone receptor-negative status, and non-luminal tumors compared to postmenopausal patients, patients with low-grade, hormone receptor-positive, and luminal disease. BRAF gain and high-level amplification copy numbers were significantly associated with higher NPI scores and larger tumor sizes compared to neutral copy number status. Survival analysis revealed no discernible differences in overall survival for patients with low and high BRAF mRNA expression. Conclusion: High BRAF mRNA expression as well as the gain and high-level amplification copy numbers were associated with advanced tumor characteristics and unfavorable prognostic factors in breast cancer. BRAF could be an appealing target for the treatment of premenopausal patients with hormone receptor-negative breast cancer.
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Affiliation(s)
- Yazan R. Alhamdan
- Department of Clinical PharmacyFaculty of PharmacyJordan University of Science and Technology, PO Box 3030, Irbid 22110, Jordan
| | - Nehad M. Ayoub
- Department of Clinical PharmacyFaculty of PharmacyJordan University of Science and Technology, PO Box 3030, Irbid 22110, Jordan
| | - Sara K. Jaradat
- Department of Clinical PharmacyFaculty of PharmacyJordan University of Science and Technology, PO Box 3030, Irbid 22110, Jordan
| | - Aymen Shatnawi
- Department of Drug Discovery and Biomedical SciencesCollege of PharmacyMedical University of South Carolina, 70 President St., Charleston, South Carolina 29425, USA
| | - Rami J. Yaghan
- Department of SurgeryCollege of Medicine and Medical SciencesArabian Gulf University, Road 2904, Building 293, Manama, Bahrain
- Department of General Surgery and UrologyFaculty of MedicineJordan University of Science and Technology, PO Box 3030, Irbid 22110, Jordan
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12
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Schillo JL, Feddersen CR, Peplinski RM, Powell LS, Varzavand A, Stipp CS, Riordan JD, Dupuy AJ. Single-cell genomics analysis reveals complex genetic interactions in an in vivo model of acquired BRAF inhibitor resistance. NAR Cancer 2024; 6:zcad061. [PMID: 38213996 PMCID: PMC10782916 DOI: 10.1093/narcan/zcad061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 11/20/2023] [Accepted: 12/21/2023] [Indexed: 01/13/2024] Open
Abstract
The evolution of therapeutic resistance is a major obstacle to the success of targeted oncology drugs. While both inter- and intratumoral heterogeneity limit our ability to detect resistant subpopulations that pre-exist or emerge during treatment, our ability to analyze tumors with single-cell resolution is limited. Here, we utilized a cell-based transposon mutagenesis method to identify mechanisms of BRAF inhibitor resistance in a model of cutaneous melanoma. This screen identified overexpression of NEDD4L and VGLL3 as significant drivers of BRAF inhibitor resistance in vivo. In addition, we describe a novel single-cell genomics profiling method to genotype thousands of individual cells within tumors driven by transposon mutagenesis. This approach revealed a surprising genetic diversity among xenograft tumors and identified recurrent co-occurring mutations that emerge within distinct tumor subclones. Taken together, these observations reveal an unappreciated genetic complexity that drives BRAF inhibitor resistance.
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Affiliation(s)
- Jacob L Schillo
- Department of Anatomy & Cell Biology, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA
- Interdisciplinary Graduate Program in Genetics, The University of Iowa, Iowa City, IA 52242, USA
| | - Charlotte R Feddersen
- Department of Anatomy & Cell Biology, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA
- Medical Scientist Training Program, The University of Iowa, Iowa City, IA 52242, USA
| | - Rebekah M Peplinski
- Department of Anatomy & Cell Biology, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA
- Interdisciplinary Graduate Program in Genetics, The University of Iowa, Iowa City, IA 52242, USA
| | - Lexy S Powell
- Department of Anatomy & Cell Biology, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA
| | - Afshin Varzavand
- Holden Comprehensive Cancer Center, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA
- Department of Biology, The University of Iowa, Iowa City, IA 52242, USA
| | - Christopher S Stipp
- Holden Comprehensive Cancer Center, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA
- Department of Biology, The University of Iowa, Iowa City, IA 52242, USA
| | - Jesse D Riordan
- Department of Anatomy & Cell Biology, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA
| | - Adam J Dupuy
- Department of Anatomy & Cell Biology, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA
- Holden Comprehensive Cancer Center, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA
- Department of Biology, The University of Iowa, Iowa City, IA 52242, USA
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13
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Underwood PW, Ruff SM, Pawlik TM. Update on Targeted Therapy and Immunotherapy for Metastatic Colorectal Cancer. Cells 2024; 13:245. [PMID: 38334637 PMCID: PMC10854977 DOI: 10.3390/cells13030245] [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: 12/27/2023] [Revised: 01/21/2024] [Accepted: 01/25/2024] [Indexed: 02/10/2024] Open
Abstract
Metastatic colorectal cancer remains a deadly malignancy and is the third leading cause of cancer-related death. The mainstay of treatment for metastatic colorectal cancer is chemotherapy, but unfortunately, even with recent progress, overall survival is still poor. Colorectal cancer is a heterogeneous disease, and the underlying genetic differences among tumors can define the behavior and prognosis of the disease. Given the limitations of cytotoxic chemotherapy, research has focused on developing targeted therapy based on molecular subtyping. Since the early 2000s, multiple targeted therapies have demonstrated efficacy in treating metastatic colorectal cancer and have received FDA approval. The epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and DNA mismatch repair pathways have demonstrated promising results for targeted therapies. As new gene mutations and proteins involved in the oncogenesis of metastatic colorectal cancer are identified, new targets will continue to emerge. We herein provide a summary of the updated literature regarding targeted therapies for patients with mCRC.
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Affiliation(s)
| | | | - Timothy M. Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, 395 W. 12th Ave., Suite 670, Columbus, OH 43210, USA; (P.W.U.); (S.M.R.)
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14
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Murali VS, Rajendran D, Isogai T, DeBerardinis RJ, Danuser G. RhoA activation promotes glucose uptake to elevate proliferation in MAPK inhibitor resistant melanoma cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.09.574940. [PMID: 38260449 PMCID: PMC10802590 DOI: 10.1101/2024.01.09.574940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2024]
Abstract
Cutaneous melanomas harboring a B-RafV600E mutation are treated with immune check point inhibitors or kinase inhibitor combination therapies relying on MAPK inhibitors (MAPKi) Dabrafenib and Trametinib (Curti and Faries, 2021). However, cells become resistant to treatments over the timespan of a few months. Resistance to MAPKi has been associated with adoption of an aggressive amoeboid phenotype characterized by elevated RhoA signaling, enhanced contractility and thick cortical filamentous actin (F-actin) structures (Kim et al., 2016; Misek et al., 2020). Targeting active RhoA through Rho-kinase (ROCK) inhibitors, either alone or in combination with immunotherapies, reverts MAPKi-resistance (Misek et al., 2020; Orgaz et al., 2020). Yet, the mechanisms for this behavior remain largely unknown. Given our recent findings of cytoskeleton's role in cancer cell proliferation (Mohan et al., 2019), survival (Weems et al., 2023), and metabolism (Park et al., 2020), we explored possibilities by which RhoA-driven changes in cytoskeleton structure may confer resistance. We confirmed elevated activation of RhoA in a panel of MAPKi-resistant melanoma cell lines, leading to a marked increase in the presence of contractile F-actin bundles. Moreover, these cells had increased glucose uptake and glycolysis, a phenotype disrupted by pharmacological perturbation of ROCK. However, glycolysis was unaffected by disruption of F-actin bundles, indicating that glycolytic stimulation in MAPKi-resistant melanoma is independent of F-actin organization. Instead, our findings highlight a mechanism in which elevated RhoA signaling activates ROCK, leading to the activation of insulin receptor substrate 1 (IRS1) and P85 of the PI3K pathway, which promotes cell surface expression of GLUT1 and elevated glucose uptake. Application of ROCK inhibitor GSK269962A results in reduced glucose uptake and glycolysis, thus impeding cell proliferation. Our study adds a mechanism to the proposed use of ROCK inhibitors for long-term treatments on MAPKi-resistant melanomas.
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Affiliation(s)
- Vasanth Siruvallur Murali
- Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX, USA
- Cecil H. and Ida Green Center for Systems Biology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Divya Rajendran
- Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX, USA
- Cecil H. and Ida Green Center for Systems Biology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Tadamoto Isogai
- Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX, USA
- Cecil H. and Ida Green Center for Systems Biology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Ralph J. DeBerardinis
- Children’s Research Institute and Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX, USA
- Howard Hughes Medical Institute, UT Southwestern Medical Center, Dallas, TX, USA
- Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX, USA
| | - Gaudenz Danuser
- Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX, USA
- Cecil H. and Ida Green Center for Systems Biology, UT Southwestern Medical Center, Dallas, TX, USA
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15
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Kuboki Y, Fakih M, Strickler J, Yaeger R, Masuishi T, Kim EJ, Bestvina CM, Kopetz S, Falchook GS, Langer C, Krauss J, Puri S, Cardona P, Chan E, Varrieur T, Mukundan L, Anderson A, Tran Q, Hong DS. Sotorasib with panitumumab in chemotherapy-refractory KRAS G12C-mutated colorectal cancer: a phase 1b trial. Nat Med 2024; 30:265-270. [PMID: 38177853 PMCID: PMC11135132 DOI: 10.1038/s41591-023-02717-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Accepted: 11/14/2023] [Indexed: 01/06/2024]
Abstract
The current third-line (and beyond) treatment options for RAS-mutant metastatic colorectal cancer have yielded limited efficacy. At the time of study start, the combination of sotorasib, a KRAS (Kirsten rat sarcoma viral oncogene homolog)-G12C inhibitor, and panitumumab, an epidermal growth factor receptor (EGFR) inhibitor, was hypothesized to overcome treatment-induced resistance. This phase 1b substudy of the CodeBreaK 101 master protocol evaluated sotorasib plus panitumumab in patients with chemotherapy-refractory KRASG12C-mutated metastatic colorectal cancer. Here, we report the results in a dose-exploration cohort and a dose-expansion cohort. Patients received sotorasib (960 mg, once daily) plus panitumumab (6 mg kg-1, once every 2 weeks). The primary endpoints were safety and tolerability. Secondary endpoints included efficacy and pharmacokinetics. Exploratory biomarkers at baseline were assessed. Forty-eight patients (dose-exploration cohort, n = 8; dose-expansion cohort, n = 40) were treated. Treatment-related adverse events of any grade and grade ≥3 occurred in 45 (94%) and 13 (27%) patients, respectively. In the dose-expansion cohort, the confirmed objective response rate was 30.0% (95% confidence interval (CI) 16.6%, 46.5%). Median progression-free survival was 5.7 months (95% CI 4.2, 7.7 months). Median overall survival was 15.2 months (95% CI 12.5 months, not estimable). Prevalent genomic coalterations included APC (84%), TP53 (74%), SMAD4 (33%), PIK3CA (28%) and EGFR (26%). Sotorasib-panitumumab demonstrated acceptable safety with promising efficacy in chemotherapy-refractory KRASG12C-mutated metastatic colorectal cancer. ClinicalTrials.gov identifier: NCT04185883 .
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Affiliation(s)
| | - Marwan Fakih
- City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | | | - Rona Yaeger
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Edward J Kim
- UC Davis Comprehensive Cancer Center, Sacramento, CA, USA
| | | | - Scott Kopetz
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Corey Langer
- University of Pennsylvania, Philadelphia, PA, USA
| | | | - Sonam Puri
- Huntsman Cancer Institute, Salt Lake City, UT, USA
| | | | | | | | | | | | - Qui Tran
- Amgen Inc., Thousand Oaks, CA, USA
| | - David S Hong
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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16
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Chapdelaine AG, Ku GC, Sun G, Ayrapetov MK. The Targeted Degradation of BRAF V600E Reveals the Mechanisms of Resistance to BRAF-Targeted Treatments in Colorectal Cancer Cells. Cancers (Basel) 2023; 15:5805. [PMID: 38136350 PMCID: PMC10741866 DOI: 10.3390/cancers15245805] [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: 11/07/2023] [Revised: 12/08/2023] [Accepted: 12/09/2023] [Indexed: 12/24/2023] Open
Abstract
The BRAF V600E mutation is frequently found in cancer. It activates the MAPK pathway and promotes cancer cell proliferation, making BRAF an excellent target for anti-cancer therapy. While BRAF-targeted therapy is highly effective for melanoma, it is often ineffective against other cancers harboring the BRAF mutation. In this study, we evaluate the effectiveness of a proteolysis targeting chimera (PROTAC), SJF-0628, in directing the degradation of mutated BRAF across a diverse panel of cancer cells and determine how these cells respond to the degradation. SJF-0628 treatment results in the degradation of BRAF V600E and a decrease in Mek activation in all cell lines tested, but the effects of the treatment on cell signaling and cell proliferation are cell-line-specific. First, BRAF degradation killed DU-4475 and Colo-205 cells via apoptosis but only partially inhibited the proliferation of other cancer cell lines. Second, SJF-0628 treatment resulted in co-degradation of MEK in Colo-205 cells but did not have the same effect in other cell lines. Finally, cell lines partially inhibited by BRAF degradation also contain other oncogenic drivers, making them multi-driver cancer cells. These results demonstrate the utility of a PROTAC to direct BRAF degradation and reveal that multi-driver oncogenesis renders some colorectal cancer cells resistant to BRAF-targeted treatment.
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Affiliation(s)
| | | | - Gongqin Sun
- Department of Cell and Molecular Biology, University of Rhode Island, Kingston, RI 02881, USA; (A.G.C.); (G.C.K.)
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17
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Saleh K, Al Sakhen M, Kanaan S, Yasin S, Höpfner M, Tahtamouni L, Biersack B. Antitumor activity of the new tyrphostin briva against BRAF V600E-mutant colorectal carcinoma cells. Invest New Drugs 2023; 41:791-801. [PMID: 37870738 DOI: 10.1007/s10637-023-01402-2] [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: 08/25/2023] [Accepted: 10/12/2023] [Indexed: 10/24/2023]
Abstract
Because of a reduced sensitivity of BRAF-mutant colorectal cancers to BRAF inhibitor treatment when compared with BRAF-mutant melanoma, it is essential to develop efficient drugs to cope with this disease. The new 2-(4-bromophenyl)-3-arylacrylonitrile compound Briva was prepared in one step from commercially available starting compounds. Briva and two known thiophene analogs (Thio-Iva and Thio-Dam) were tested for their cytotoxic activity against various tumor cell lines including colorectal and breast cancer cells. The antitumor activities of the test compounds were assessed in vitro via the MTT assay, DAPI staining of nuclei, RT-PCR and immunoblotting, wound healing, clonogenic assay, collagen I adhesion assay, and kinase inhibition assays. A selective activity of Briva was observed against BRAFV600E-mutant HT-29 and COLO-201 colorectal carcinoma (CRC) cells. Briva caused inhibition of HT-29 clonogenic tumor growth and was found to induce cytotoxicity by activating the intrinsic apoptosis pathway. In addition, Briva reduced HT-29 cell adhesion and migration. Kinase inhibition experiments revealed that Briva inhibits VEGFR2. Thus, Briva can be considered as a promising antitumor compound against BRAFV600E-mutant colon carcinoma by targeting VEGFR2 tyrosine kinase and consequently reducing cell adhesion and metastasis formation.
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Affiliation(s)
- Khaled Saleh
- Department of Biology and Biotechnology, Faculty of Science, The Hashemite University, Zarqa, 13115, Jordan
| | - Mai Al Sakhen
- Department of Biology and Biotechnology, Faculty of Science, The Hashemite University, Zarqa, 13115, Jordan
| | - Sana Kanaan
- Department of Biology and Biotechnology, Faculty of Science, The Hashemite University, Zarqa, 13115, Jordan
| | - Salem Yasin
- Department of Biology and Biotechnology, Faculty of Science, The Hashemite University, Zarqa, 13115, Jordan
| | - Michael Höpfner
- Institute of Physiology, Charité-Universitätsmedizin Berlin, Corporate Member of the Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany
| | - Lubna Tahtamouni
- Department of Biology and Biotechnology, Faculty of Science, The Hashemite University, Zarqa, 13115, Jordan.
- Department of Biochemistry and Molecular Biology, College of Natural Sciences, Colorado State University, Fort Collins, CO, 80526, USA.
| | - Bernhard Biersack
- Organic Chemistry Laboratory, University Bayreuth, Universitätsstrasse 30, 95440, Bayreuth, Germany.
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18
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Chen W, Park JI. Tumor Cell Resistance to the Inhibition of BRAF and MEK1/2. Int J Mol Sci 2023; 24:14837. [PMID: 37834284 PMCID: PMC10573597 DOI: 10.3390/ijms241914837] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 09/26/2023] [Accepted: 09/27/2023] [Indexed: 10/15/2023] Open
Abstract
BRAF is one of the most frequently mutated oncogenes, with an overall frequency of about 50%. Targeting BRAF and its effector mitogen-activated protein kinase kinase 1/2 (MEK1/2) is now a key therapeutic strategy for BRAF-mutant tumors, and therapies based on dual BRAF/MEK inhibition showed significant efficacy in a broad spectrum of BRAF tumors. Nonetheless, BRAF/MEK inhibition therapy is not always effective for BRAF tumor suppression, and significant challenges remain to improve its clinical outcomes. First, certain BRAF tumors have an intrinsic ability to rapidly adapt to the presence of BRAF and MEK1/2 inhibitors by bypassing drug effects via rewired signaling, metabolic, and regulatory networks. Second, almost all tumors initially responsive to BRAF and MEK1/2 inhibitors eventually acquire therapy resistance via an additional genetic or epigenetic alteration(s). Overcoming these challenges requires identifying the molecular mechanism underlying tumor cell resistance to BRAF and MEK inhibitors and analyzing their specificity in different BRAF tumors. This review aims to update this information.
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Affiliation(s)
| | - Jong-In Park
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA;
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19
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Inagaki C, Matoba R, Yuki S, Shiozawa M, Tsuji A, Inoue E, Muro K, Ichikawa W, Fujii M, Sunakawa Y. The BEETS (JACCRO CC-18) trial: an observational and translational study of BRAF-mutated metastatic colorectal cancer. Future Oncol 2023; 19:1165-1174. [PMID: 37458152 DOI: 10.2217/fon-2023-0209] [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: 03/15/2023] [Accepted: 05/26/2023] [Indexed: 07/18/2023] Open
Abstract
For BRAF V600E-mutated metastatic colorectal cancer (mCRC), the BEACON phase 3 trial showed survival benefit of triplet therapy with cetuximab (anti-EGFR antibody), encorafenib (BRAF inhibitor) and binimetinib (MEK inhibitor) as well as doublet therapy with cetuximab and encorafenib over irinotecan-based chemotherapy plus anti-EGFR antibody. Both regimens are standards of care in Japan, but definite biomarkers for predicting efficacy and selecting treatment remain lacking. The mechanisms underlying resistance to these regimens also warrant urgent exploration to further evolve treatment. This prospective observational/translational study evaluated real-word clinical outcomes with cetuximab and encorafenib with or without binimetinib for BRAF-mutated mCRC patients and investigated biomarkers for response and resistance by collecting blood samples before and after treatment. Clinical Trial Registration: UMIN000045530 (https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000051983).
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Affiliation(s)
- Chiaki Inagaki
- Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osakasayama, Osaka 589-8511, Japan
| | - Ryo Matoba
- DNA Chip Research Inc., 1-15-1, Kaigan, Minato-ku, Tokyo 105-0022, Japan
| | - Satoshi Yuki
- Department of Gastroenterology & Hepatology, Hokkaido University Hospital, Kita 14, Nishi 5, Kita-ku, Sapporo, Hokkaido 060-8648, Japan
| | - Manabu Shiozawa
- Department of Surgery, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi Ward, Yokohama, Kanagawa 241-8515, Japan
| | - Akihito Tsuji
- Department of Clinical Oncology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan
| | - Eisuke Inoue
- Showa University Research Administration Center, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
| | - Kei Muro
- Department of Clinical Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi 464-8681, Japan
| | - Wataru Ichikawa
- Division of Medical Oncology, Showa University Fujigaoka Hospital, 1-30 Fujigaoka, Aoba-ku, Yokohama, Kanagawa 227-8501, Japan
| | - Masashi Fujii
- Japan Clinical Cancer Research Organization (JACCRO), 1-64 Kanda-Jimbocho, Chiyoda-ku, Tokyo 101-0051, Japan
| | - Yu Sunakawa
- Department of Clinical Oncology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan
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20
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Van Cutsem E, Taieb J, Yaeger R, Yoshino T, Grothey A, Maiello E, Elez E, Dekervel J, Ross P, Ruiz-Casado A, Graham J, Kato T, Ruffinelli JC, André T, Carrière Roussel E, Klauck I, Groc M, Vedovato JC, Tabernero J. ANCHOR CRC: Results From a Single-Arm, Phase II Study of Encorafenib Plus Binimetinib and Cetuximab in Previously Untreated BRAFV600E-Mutant Metastatic Colorectal Cancer. J Clin Oncol 2023; 41:2628-2637. [PMID: 36763936 PMCID: PMC10414717 DOI: 10.1200/jco.22.01693] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 11/12/2022] [Accepted: 12/27/2022] [Indexed: 02/12/2023] Open
Abstract
PURPOSE The positive BEACON colorectal cancer (CRC) safety lead-in, evaluating encorafenib + cetuximab + binimetinib in previously treated patients with BRAFV600E-mutated metastatic CRC (mCRC), prompted the design of the phase II ANCHOR CRC study (ClinicalTrails.gov identifier: NCT03693170). ANCHOR CRC aimed to evaluate efficacy, safety, and quality of life with first-line encorafenib + binimetinib + cetuximab in BRAFV600E-mutated mCRC. METHODS In this multicenter, open-label, single-arm study, patients with BRAFV600E-mutated mCRC received oral encorafenib 300 mg once daily and binimetinib 45 mg twice daily in 28-day cycles, plus intravenous cetuximab 400 mg/m2 once on day 1 of cycle 1, then 250 mg/m2 once weekly for the first seven cycles, and 500 mg/m2 once on Days 1 and 15 from cycle 8 onward. The primary end point was locally assessed confirmed objective response rate (cORR), and secondary end points included centrally assessed cORR, progression-free survival, overall survival (OS), quality of life, and safety and tolerability. RESULTS Among 95 patients, the locally assessed cORR was 47.4% (95% CI, 37.0 to 57.9) with all partial responses. Since the lower limit of the 95% CI exceeded 30%, the primary end point was met. With a median follow-up duration of 20.1 months, the median progression-free survival on the basis of local assessments was 5.8 months and the median OS was 18.3 months. Treatment was well tolerated, with no unexpected toxicities. Using Patient Global Impression of Changes, substantial improvement in symptoms was consistently reported in ≥ 30% of patients from cycle 3 to cycle 10. CONCLUSION The ANCHOR CRC study showed that the scientifically driven combination of encorafenib + binimetinib + cetuximab was active in the first-line setting of BRAFV600E-mutated mCRC with a manageable safety profile. Further first-line evaluation is ongoing (ClinicalTrails.gov identifier: NCT04607421).
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Affiliation(s)
| | - Julien Taieb
- Department of Hepatogastroenterology and Gastrointestinal Oncology, University Paris-cité (Paris Descartes), SIRIC CARPEM, Georges Pompidou European Hospital, AP-HP, Paris, France
| | - Rona Yaeger
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Axel Grothey
- West Cancer Center and Research Institute, Germantown, TN
| | - Evaristo Maiello
- Oncology Unit, Foundation IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy
| | - Elena Elez
- Department of Medical Oncology, Vall d’Hebron Barcelona Hospital Campus, Vall d’Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain
| | | | - Paul Ross
- Department of Oncology, Guy's & St Thomas' NHS Foundation Trust, London, UK
| | - Ana Ruiz-Casado
- Hospital Universitario Puerta de Hierro Majadahonda, IDIPHISA, Madrid, Spain
| | - Janet Graham
- Dept of Medical Oncology, Beatson West of Scotland Cancer Centre and University of Glasgow, Glasgow, UK
| | - Takeshi Kato
- Department of Colorectal Surgery, National Hospital Organization, Osaka National Hospital, Osaka, Japan
| | - Jose C. Ruffinelli
- Institut Català dˊOncologia LˊHospitalet–Hospital, Duran i Reynals, Barcelona, Spain
| | - Thierry André
- Sorbonne University; Department of Medical Oncology, Saint-Antoine Hospital, AP-HP, Paris, France
| | | | - Isabelle Klauck
- Pierre Fabre, Medical & Patient/Consumer Division, Boulogne, France
| | - Mélanie Groc
- Pierre Fabre, Medical & Patient/Consumer Division, Langlade, France
| | | | - Josep Tabernero
- Department of Medical Oncology, Vall d’Hebron Barcelona Hospital, Vall d’Hebron Institute of Oncology (VHIO), IOB-Quiron, UVic-UCC, Barcelona, Spain
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21
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Morimoto Y, Yamashita N, Hirose H, Fushimi A, Haratake N, Daimon T, Bhattacharya A, Ahmad R, Suzuki Y, Takahashi H, Kufe DW. MUC1-C is necessary for SHP2 activation and BRAF inhibitor resistance in BRAF(V600E) mutant colorectal cancer. Cancer Lett 2023; 559:216116. [PMID: 36878307 PMCID: PMC10408991 DOI: 10.1016/j.canlet.2023.216116] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 02/19/2023] [Accepted: 03/02/2023] [Indexed: 03/07/2023]
Abstract
Colorectal cancers (CRCs) harboring the BRAF(V600E) mutation are associated with aggressive disease and resistance to BRAF inhibitors by feedback activation of the receptor tyrosine kinase (RTK)→RAS→MAPK pathway. The oncogenic MUC1-C protein promotes progression of colitis to CRC; whereas there is no known involvement of MUC1-C in BRAF(V600E) CRCs. The present work demonstrates that MUC1 expression is significantly upregulated in BRAF(V600E) vs wild-type CRCs. We show that BRAF(V600E) CRC cells are dependent on MUC1-C for proliferation and BRAF inhibitor (BRAFi) resistance. Mechanistically, MUC1-C integrates induction of MYC in driving cell cycle progression with activation of the SHP2 phosphotyrosine phosphatase, which enhances RTK-mediated RAS→ERK signaling. We demonstrate that targeting MUC1-C genetically and pharmacologically suppresses (i) activation of MYC, (ii) induction of the NOTCH1 stemness factor, and (iii) the capacity for self-renewal. We also show that MUC1-C associates with SHP2 and is required for SHP2 activation in driving BRAFi-induced feedback of ERK signaling. In this way, targeting MUC1-C in BRAFi-resistant BRAF(V600E) CRC tumors inhibits growth and sensitizes to BRAF inhibition. These findings demonstrate that MUC1-C is a target for the treatment of BRAF(V600E) CRCs and for reversing their resistance to BRAF inhibitors by suppressing the feedback MAPK pathway.
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Affiliation(s)
| | - Nami Yamashita
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Haruka Hirose
- Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan
| | - Atsushi Fushimi
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Naoki Haratake
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Tatsuaki Daimon
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | | | - Rehan Ahmad
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Yozo Suzuki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Hidekazu Takahashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Donald W Kufe
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
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22
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Hendrikse CSE, Theelen PMM, van der Ploeg P, Westgeest HM, Boere IA, Thijs AMJ, Ottevanger PB, van de Stolpe A, Lambrechts S, Bekkers RLM, Piek JMJ. The potential of RAS/RAF/MEK/ERK (MAPK) signaling pathway inhibitors in ovarian cancer: A systematic review and meta-analysis. Gynecol Oncol 2023; 171:83-94. [PMID: 36841040 DOI: 10.1016/j.ygyno.2023.01.038] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 01/01/2023] [Accepted: 01/30/2023] [Indexed: 02/27/2023]
Abstract
BACKGROUND The RAS/RAF/MEK/ERK (MAPK) pathway plays a role in ovarian carcinogenesis. Low-grade serous ovarian carcinoma (LGSOC) frequently harbors activating MAPK mutations. MAPK inhibitors have been used in small subsets of ovarian carcinoma (OC) patients to control tumor growth. Therefore, we performed a meta-analysis to evaluate the effectiveness of MAPK inhibitors in OC patients. We aimed to determine the clinical benefit rate (CBR), the subgroup of MAPK inhibitors with the best CBR and overall response rate (ORR), and the most common adverse events. METHODS We conducted a search in PubMed, Embase via Ovid, the Cochrane library and clinicaltrials.gov on studies evaluating the efficacy of single MAPK pathway inhibition with MAPK pathway inhibitors in OC patients. Our primary outcome included the CBR, defined by the proportion of patients with stable disease (SD), complete (CR) and partial response (PR). Secondary outcomes included the ORR (including PR and CR) and grade 3 and 4 adverse events. Meta-analysis was performed using a random-effects model. RESULTS We included nine studies with a total of 319 OC patients, for which we determined a pooled CBR of 63% (95%-CI 39-84%, I2 = 92%). Combined treatment with Raf- and MEK inhibitors in in BRAFv600 mutated LGSOC (n = 6) had the greatest efficacy with a CBR of 100% and ORR of 83%. MEK inhibitors had the best efficacy as a single agent. Subgroup analysis by tumor histology demonstrated a significantly higher CBR and ORR in patients with LGSOC, with a pooled CBR and ORR of 87% (95%-CI 81-92%, I2 = 0%) and 27% (95%-CI 10-48%, I2 = 77%) respectively. Adverse events of grade 3 or higher were reported frequently: 123 in 167 patients. CONCLUSIONS MEK inhibitors are the most promising single agents in (LGS)OC. However, dual MAPK pathway inhibition should be considered in patients with a BRAFv600 mutation, or non-mutated OC with depleted treatment options due indications of higher efficacy and tolerable toxicity profiles.
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Affiliation(s)
- C S E Hendrikse
- Department of Obstetrics and Gynecology and Catharina Cancer Institute, Catharina Hospital, Eindhoven, the Netherlands; GROW School for Oncology and Reproduction, Maastricht University, Maastricht, the Netherlands.
| | - P M M Theelen
- Department of Obstetrics and Gynecology and Catharina Cancer Institute, Catharina Hospital, Eindhoven, the Netherlands
| | - P van der Ploeg
- Department of Obstetrics and Gynecology and Catharina Cancer Institute, Catharina Hospital, Eindhoven, the Netherlands; GROW School for Oncology and Reproduction, Maastricht University, Maastricht, the Netherlands
| | - H M Westgeest
- Department of Internal Medicine, Amphia Hospital, Breda, the Netherlands
| | - I A Boere
- Department of Medical Oncology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands
| | - A M J Thijs
- Department of Internal Medicine and Catharina Cancer Institute, Catharina Hospital, Eindhoven, the Netherlands
| | - P B Ottevanger
- Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - A van de Stolpe
- Drug Companion Diagnostics Company - Therapeutics (DCDC-Tx), Vught, the Netherlands
| | - S Lambrechts
- Department of Obstetrics and Gynecology, Maastricht University Medical Center+, Maastricht, the Netherlands
| | - R L M Bekkers
- Department of Obstetrics and Gynecology and Catharina Cancer Institute, Catharina Hospital, Eindhoven, the Netherlands; GROW School for Oncology and Reproduction, Maastricht University, Maastricht, the Netherlands
| | - J M J Piek
- Department of Obstetrics and Gynecology and Catharina Cancer Institute, Catharina Hospital, Eindhoven, the Netherlands
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23
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Verzijl CRC, van de Peppel IP, Eilers RE, Bloks VW, Wolters JC, Koehorst M, Kloosterhuis NJ, Havinga R, Jalving M, Struik D, Jonker JW. Pharmacological inhibition of MEK1/2 signaling disrupts bile acid metabolism through loss of Shp and enhanced Cyp7a1 expression. Biomed Pharmacother 2023; 159:114270. [PMID: 36680812 DOI: 10.1016/j.biopha.2023.114270] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 01/06/2023] [Accepted: 01/16/2023] [Indexed: 01/21/2023] Open
Abstract
The RAS-MAPK signaling pathway is one of the most frequently dysregulated pathways in human cancer. Small molecule inhibitors directed against this pathway have clinical activity in patients with various cancer types and can improve patient outcomes. However, the use of these drugs is associated with adverse effects, which can result in dose reduction or treatment interruption. A better molecular understanding of on-target, off-tumor effects may improve toxicity management. In the present study, we aimed to identify early initiating biological changes in the liver upon pharmacological inhibition of the RAS-MAPK signaling pathway. To this end, we tested the effect of MEK inhibitor PD0325901 using mice and human hepatocyte cell lines. Male C57BL/6 mice were treated with either vehicle or PD0325901 for six days, followed by transcriptome analysis of the liver and phenotypic characterization. Pharmacological MEK inhibition altered the expression of 423 genes, of which 78 were upregulated and 345 were downregulated. We identified Shp, a transcriptional repressor, and Cyp7a1, the rate-limiting enzyme in converting cholesterol to bile acids, as the top differentially expressed genes. PD0325901 treatment also affected other genes involved in bile acid regulation, which was associated with changes in the composition of plasma bile acids and composition and total levels of fecal bile acids and elevated predictive biomarkers of early liver toxicity. In conclusion, short-term pharmacological MEK inhibition results in profound changes in bile acid metabolism, which may explain some of the clinical adverse effects of pharmacological inhibition of the RAS-MAPK pathway, including gastrointestinal complications and hepatotoxicity.
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Affiliation(s)
- Cristy R C Verzijl
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Ivo P van de Peppel
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Roos E Eilers
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Vincent W Bloks
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Justina C Wolters
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Martijn Koehorst
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, 9713 Groningen, GZ, The Netherlands
| | - Niels J Kloosterhuis
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Rick Havinga
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Mathilde Jalving
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Dicky Struik
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Johan W Jonker
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
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24
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Meng Q, Zhao J, Yu Y, Wang K, Ren J, Xu C, Wang Y, Wang G. Survival comparison of first-line treatment regimens in patients with braf-mutated advanced colorectal cancer: a multicenter retrospective study. BMC Cancer 2023; 23:191. [PMID: 36849918 PMCID: PMC9969634 DOI: 10.1186/s12885-023-10640-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 02/13/2023] [Indexed: 03/01/2023] Open
Abstract
BACKGROUND Patients with V-Raf murine sarcoma viral oncogene homolog B1 (BRAF) V600E-mutated advanced colorectal cancer (CRC) have a poor prognosis, and treatment options that can improve outcome are still under investigation. The purpose of this study was to discuss the differences of overall survival (OS) and progression-free survival (PFS) between patients with BRAF V600E-mutated advanced CRC who were treated with chemotherapy alone and chemotherapy combined with targeted therapy in advanced first-line therapy. METHODS Grouping of 61 patients according to first-line treatment regimen (chemotherapy alone/chemotherapy combined with bevacizumab). Kaplan-Meier method and log-rank test were used to compare OS and PFS. Cox proportional hazards regression model was used to measure the risk of first-line medication therapies while correcting for confounding factors that may affect PFS and OS. RESULTS There was no significant difference in OS between patients treated with chemotherapy alone and those treated with chemotherapy combined with bevacizumab (P = 0.93; HR, 1.027; 95% CI, 0.555-1.901). Likewise, there was no significant difference in PFS between the two groups (P = 0.29; HR, 0.734; 95% CI, 0.413-1.304). Subgroup analysis showed that OS and PFS of different treatment regimens were not significantly different among subgroups. Multivariate analysis suggested that surgical treatment of primary tumor (P = 0.001; HR, 0.326; 95% CI, 0.169-0.631) and presence of liver metastasis (P = 0.009; HR, 2.399; 95% CI, 1.242-4.635) may serve as independent prognostic indicators in patients with BRAF-mutated advanced CRC. Surgical treatment of the primary tumor (P = 0.041; HR, 0.523; 95% CI, 0.280-0.974) was significantly associated with PFS too. CONCLUSION For patients with BRAF V600E-mutated advanced CRC, chemotherapy alone did not differ significantly in OS and PFS compared with chemotherapy + bevacizumab for advanced first-line therapy. Chemotherapy combined with targeted therapy did not render a survival benefit to these patients, demonstrating that the importance of developing new treatment options for this population.
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Affiliation(s)
- Qianhao Meng
- grid.412651.50000 0004 1808 3502Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150040 People’s Republic of China
| | - Jian Zhao
- grid.263452.40000 0004 1798 4018Department of Digestive, Shanxi Province Cancer Hospital/ Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi 030013 People’s Republic of China
| | - Yuanyuan Yu
- grid.412651.50000 0004 1808 3502Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150040 People’s Republic of China
| | - Ke Wang
- grid.412651.50000 0004 1808 3502Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150040 People’s Republic of China
| | - Jing Ren
- grid.412651.50000 0004 1808 3502Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150040 People’s Republic of China
| | - Chang Xu
- grid.412651.50000 0004 1808 3502Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150040 People’s Republic of China
| | - Yusheng Wang
- Department of Digestive, Shanxi Province Cancer Hospital/ Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, 030013, People's Republic of China.
| | - Guangyu Wang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150040, People's Republic of China.
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25
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Tian J, Chen JH, Chao SX, Pelka K, Giannakis M, Hess J, Burke K, Jorgji V, Sindurakar P, Braverman J, Mehta A, Oka T, Huang M, Lieb D, Spurrell M, Allen JN, Abrams TA, Clark JW, Enzinger AC, Enzinger PC, Klempner SJ, McCleary NJ, Meyerhardt JA, Ryan DP, Yurgelun MB, Kanter K, Van Seventer EE, Baiev I, Chi G, Jarnagin J, Bradford WB, Wong E, Michel AG, Fetter IJ, Siravegna G, Gemma AJ, Sharpe A, Demehri S, Leary R, Campbell CD, Yilmaz O, Getz GA, Parikh AR, Hacohen N, Corcoran RB. Combined PD-1, BRAF and MEK inhibition in BRAF V600E colorectal cancer: a phase 2 trial. Nat Med 2023; 29:458-466. [PMID: 36702949 PMCID: PMC9941044 DOI: 10.1038/s41591-022-02181-8] [Citation(s) in RCA: 99] [Impact Index Per Article: 49.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Accepted: 12/12/2022] [Indexed: 01/27/2023]
Abstract
While BRAF inhibitor combinations with EGFR and/or MEK inhibitors have improved clinical efficacy in BRAFV600E colorectal cancer (CRC), response rates remain low and lack durability. Preclinical data suggest that BRAF/MAPK pathway inhibition may augment the tumor immune response. We performed a proof-of-concept single-arm phase 2 clinical trial of combined PD-1, BRAF and MEK inhibition with sparatlizumab (PDR001), dabrafenib and trametinib in 37 patients with BRAFV600E CRC. The primary end point was overall response rate, and the secondary end points were progression-free survival, disease control rate, duration of response and overall survival. The study met its primary end point with a confirmed response rate (24.3% in all patients; 25% in microsatellite stable patients) and durability that were favorable relative to historical controls of BRAF-targeted combinations alone. Single-cell RNA sequencing of 23 paired pretreatment and day 15 on-treatment tumor biopsies revealed greater induction of tumor cell-intrinsic immune programs and more complete MAPK inhibition in patients with better clinical outcome. Immune program induction in matched patient-derived organoids correlated with the degree of MAPK inhibition. These data suggest a potential tumor cell-intrinsic mechanism of cooperativity between MAPK inhibition and immune response, warranting further clinical evaluation of optimized targeted and immune combinations in CRC. ClinicalTrials.gov registration: NCT03668431.
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Affiliation(s)
- Jun Tian
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA
| | - Jonathan H Chen
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA
- The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
| | - Sherry X Chao
- The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
| | - Karin Pelka
- The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
- Gladstone-UCSF Institute of Genomic Immunology, Gladstone Institutes Department of Microbiology and Immunology, UCSF, San Francisco, CA, USA
| | - Marios Giannakis
- Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
| | - Julian Hess
- The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
| | - Kelly Burke
- Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
| | - Vjola Jorgji
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA
| | - Princy Sindurakar
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA
| | - Jonathan Braverman
- The Koch Institute, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Arnav Mehta
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA
- The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
| | - Tomonori Oka
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA
| | - Mei Huang
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA
| | - David Lieb
- The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
| | - Maxwell Spurrell
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA
| | - Jill N Allen
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA
| | - Thomas A Abrams
- Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
| | - Jeffrey W Clark
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA
| | - Andrea C Enzinger
- Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
| | - Peter C Enzinger
- Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
| | - Samuel J Klempner
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA
| | - Nadine J McCleary
- Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
| | | | - David P Ryan
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA
| | - Matthew B Yurgelun
- Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
| | - Katie Kanter
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA
| | - Emily E Van Seventer
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA
| | - Islam Baiev
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA
| | - Gary Chi
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA
| | - Joy Jarnagin
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA
| | - William B Bradford
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA
| | - Edmond Wong
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA
| | - Alexa G Michel
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA
| | - Isobel J Fetter
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA
| | - Giulia Siravegna
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA
| | - Angelo J Gemma
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA
| | - Arlene Sharpe
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Shadmehr Demehri
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA
| | - Rebecca Leary
- Novartis Institute for Biomedical Research, Cambridge, MA, USA
| | | | - Omer Yilmaz
- The Koch Institute, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Gad A Getz
- The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
| | - Aparna R Parikh
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA
| | - Nir Hacohen
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA.
- The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
| | - Ryan B Corcoran
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA.
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Song Y, Bi Z, Liu Y, Qin F, Wei Y, Wei X. Targeting RAS-RAF-MEK-ERK signaling pathway in human cancer: Current status in clinical trials. Genes Dis 2023; 10:76-88. [PMID: 37013062 PMCID: PMC10066287 DOI: 10.1016/j.gendis.2022.05.006] [Citation(s) in RCA: 96] [Impact Index Per Article: 48.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 04/23/2022] [Accepted: 05/05/2022] [Indexed: 12/12/2022] Open
Abstract
Molecular target inhibitors have been regularly approved by Food and Drug Administration (FDA) for tumor treatment, and most of them intervene in tumor cell proliferation and metabolism. The RAS-RAF-MEK-ERK pathway is a conserved signaling pathway that plays vital roles in cell proliferation, survival, and differentiation. The aberrant activation of the RAS-RAF-MEK-ERK signaling pathway induces tumors. About 33% of tumors harbor RAS mutations, while 8% of tumors are driven by RAF mutations. Great efforts have been dedicated to targeting the signaling pathway for cancer treatment in the past decades. In this review, we summarized the development of inhibitors targeting the RAS-RAF-MEK-ERK pathway with an emphasis on those used in clinical treatment. Moreover, we discussed the potential combinations of inhibitors that target the RAS-RAF-MEK-ERK signaling pathway and other signaling pathways. The inhibitors targeting the RAS-RAF-MEK-ERK pathway have essentially modified the therapeutic strategy against various cancers and deserve more attention in the current cancer research and treatment.
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Affiliation(s)
| | | | - Yu Liu
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Furong Qin
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yuquan Wei
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Xiawei Wei
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
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27
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Recent and Future Strategies to Overcome Resistance to Targeted Therapies and Immunotherapies in Metastatic Colorectal Cancer. J Clin Med 2022; 11:jcm11247523. [PMID: 36556139 PMCID: PMC9783354 DOI: 10.3390/jcm11247523] [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: 11/02/2022] [Revised: 12/06/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common cause of cancer-related deaths worldwide, and 20% of patients with CRC present at diagnosis with metastases. The treatment of metastatic CRC is based on a fluoropyrimidine-based chemotherapy plus additional agents such as oxaliplatin and irinotecan. To date, on the basis of the molecular background, targeted therapies (e.g., monoclonal antibodies against epidermal growth factor receptor or inhibiting angiogenesis) are administered to improve the treatment of metastatic CRC. In addition, more recently, immunological agents emerged as effective in patients with a defective mismatch repair system. The administration of targeted therapies and immunotherapy lead to a significant increase in the survival of patients; however these drugs do not always prove effective. In most cases the lack of effectiveness is due to the development of primary resistance, either a resistance-inducing factor is already present before treatment or resistance is acquired when it occurs after treatment initiation. In this review we describe the most relevant targeted therapies and immunotherapies and expand on the reasons for resistance to the different approved or under development targeted drugs. Then we showed the possible mechanisms and drugs that may lead to overcoming the primary or acquired resistance in metastatic CRC.
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28
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Channathodiyil P, May K, Segonds-Pichon A, Smith PD, Cook S, Houseley J. Escape from G1 arrest during acute MEK inhibition drives the acquisition of drug resistance. NAR Cancer 2022; 4:zcac032. [PMID: 36267209 PMCID: PMC9575185 DOI: 10.1093/narcan/zcac032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 09/08/2022] [Accepted: 10/04/2022] [Indexed: 11/13/2022] Open
Abstract
Mutations and gene amplifications that confer drug resistance emerge frequently during chemotherapy, but their mechanism and timing are poorly understood. Here, we investigate BRAFV600E amplification events that underlie resistance to the MEK inhibitor selumetinib (AZD6244/ARRY-142886) in COLO205 cells, a well-characterized model for reproducible emergence of drug resistance, and show that BRAF amplifications acquired de novo are the primary cause of resistance. Selumetinib causes long-term G1 arrest accompanied by reduced expression of DNA replication and repair genes, but cells stochastically re-enter the cell cycle during treatment despite continued repression of pERK1/2. Most DNA replication and repair genes are re-expressed as cells enter S and G2; however, mRNAs encoding a subset of factors important for error-free replication and chromosome segregation, including TIPIN, PLK2 and PLK3, remain at low abundance. This suggests that DNA replication following escape from G1 arrest in drug is more error prone and provides a potential explanation for the DNA damage observed under long-term RAF-MEK-ERK1/2 pathway inhibition. To test the hypothesis that escape from G1 arrest in drug promotes de novo BRAF amplification, we exploited the combination of palbociclib and selumetinib. Combined treatment with selumetinib and a dose of palbociclib sufficient to reinforce G1 arrest in selumetinib-sensitive cells, but not to impair proliferation of resistant cells, delays the emergence of resistant colonies, meaning that escape from G1 arrest is critical in the formation of resistant clones. Our findings demonstrate that acquisition of MEK inhibitor resistance often occurs through de novo gene amplification and can be suppressed by impeding cell cycle entry in drug.
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Affiliation(s)
| | - Kieron May
- Epigenetics Programme, Babraham Institute, Cambridge, CB22 4NT, UK
| | | | - Paul D Smith
- Oncology R&D, AstraZeneca CRUK Cambridge Institute, Cambridge, CB2 0AA, UK
| | - Simon J Cook
- Signalling Programme, Babraham Institute, Cambridge, CB22 4NT, UK
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Rubanov A, Berico P, Hernando E. Epigenetic Mechanisms Underlying Melanoma Resistance to Immune and Targeted Therapies. Cancers (Basel) 2022; 14:cancers14235858. [PMID: 36497341 PMCID: PMC9738385 DOI: 10.3390/cancers14235858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 11/22/2022] [Indexed: 11/30/2022] Open
Abstract
Melanoma is an aggressive skin cancer reliant on early detection for high likelihood of successful treatment. Solar UV exposure transforms melanocytes into highly mutated tumor cells that metastasize to the liver, lungs, and brain. Even upon resection of the primary tumor, almost thirty percent of patients succumb to melanoma within twenty years. Identification of key melanoma genetic drivers led to the development of pharmacological BRAFV600E and MEK inhibitors, significantly improving metastatic patient outcomes over traditional cytotoxic chemotherapy or pioneering IFN-α and IL-2 immune therapies. Checkpoint blockade inhibitors releasing the immunosuppressive effects of CTLA-4 or PD-1 proved to be even more effective and are the standard first-line treatment. Despite these major improvements, durable responses to immunotherapy and targeted therapy have been hindered by intrinsic or acquired resistance. In addition to gained or selected genetic alterations, cellular plasticity conferred by epigenetic reprogramming is emerging as a driver of therapy resistance. Epigenetic regulation of chromatin accessibility drives gene expression and establishes distinct transcriptional cell states. Here we review how aberrant chromatin, transcriptional, and epigenetic regulation contribute to therapy resistance and discuss how targeting these programs sensitizes melanoma cells to immune and targeted therapies.
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Affiliation(s)
- Andrey Rubanov
- Department of Pathology, NYU Grossman School of Medicine, New York, NY 10016, USA
- Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, NYU Langone Health, New York, NY 10016, USA
| | - Pietro Berico
- Department of Pathology, NYU Grossman School of Medicine, New York, NY 10016, USA
- Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, NYU Langone Health, New York, NY 10016, USA
| | - Eva Hernando
- Department of Pathology, NYU Grossman School of Medicine, New York, NY 10016, USA
- Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, NYU Langone Health, New York, NY 10016, USA
- Correspondence:
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Klute KA, Rothe M, Garrett-Mayer E, Mangat PK, Nazemzadeh R, Yost KJ, Duvivier HL, Ahn ER, Cannon TL, Alese OB, Krauss JC, Thota R, Calfa CJ, Denlinger CS, O'Lone R, Halabi S, Grantham GN, Schilsky RL. Cobimetinib Plus Vemurafenib in Patients With Colorectal Cancer With BRAF Mutations: Results From the Targeted Agent and Profiling Utilization Registry (TAPUR) Study. JCO Precis Oncol 2022; 6:e2200191. [DOI: 10.1200/po.22.00191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
PURPOSE TAPUR is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer and genomic alterations known to be drug targets. The results of a cohort of patients with colorectal cancer (CRC) with BRAF mutations treated with cobimetinib (C) plus vemurafenib (V) are reported. METHODS Eligible patients had advanced CRC, no standard treatment options, measurable disease (RECIST), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, tumors with BRAF V600E/D/K/R mutations, and no MAP2K1/2, MEK1/2, or NRAS mutations. C was taken 60 mg orally once daily for 21 days followed by seven days off, and V was taken 960 mg orally twice daily. Simon's two-stage design was used with a primary study end point of objective response or stable disease of at least 16 weeks duration. Secondary end points were progression-free survival, overall survival, and safety. RESULTS Thirty patients were enrolled from August 2016 to August 2018; all had CRC with a BRAF V600E mutation except one patient with a BRAF K601E mutation. Three patients were not evaluable for efficacy. Eight patients with partial responses and six patients with stable disease of at least 16 weeks duration were observed for disease control and objective response rates of 52% (95% CI, 35 to 65) and 30% (95% CI, 14 to 50), respectively. The null hypothesis of 15% disease control rate was rejected ( P < .0001). Thirteen patients had at least one grade 3 adverse event or serious adverse event at least possibly related to C + V: anemia, decreased lymphocytes, dyspnea, diarrhea, elevated liver enzymes, fatigue, hypercalcemia, hypophosphatemia, rash, photosensitivity, and upper gastrointestinal hemorrhage. CONCLUSION The combination of C + V has antitumor activity in heavily pretreated patients with CRC with BRAF mutations.
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Affiliation(s)
| | - Michael Rothe
- American Society of Clinical Oncology, Alexandria, VA
| | | | - Pam K. Mangat
- American Society of Clinical Oncology, Alexandria, VA
| | | | | | - Herbert L. Duvivier
- Cancer Treatment Centers of America—Atlanta, a part of City of Hope, Newnan, GA
| | - Eugene R. Ahn
- Cancer Treatment Centers of America—Chicago, a part of City of Hope, Zion, IL
| | | | | | - John C. Krauss
- University of Michigan Rogel Cancer Center, Ann Arbor, MI
| | | | - Carmen J. Calfa
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Plantation, FL
| | | | - Raegan O'Lone
- American Society of Clinical Oncology, Alexandria, VA
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NAD/NAMPT and mTOR Pathways in Melanoma: Drivers of Drug Resistance and Prospective Therapeutic Targets. Int J Mol Sci 2022; 23:ijms23179985. [PMID: 36077374 PMCID: PMC9456568 DOI: 10.3390/ijms23179985] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 08/29/2022] [Accepted: 08/30/2022] [Indexed: 11/16/2022] Open
Abstract
Malignant melanoma represents the most fatal skin cancer due to its aggressive behavior and high metastatic potential. The introduction of BRAF/MEK inhibitors and immune-checkpoint inhibitors (ICIs) in the clinic has dramatically improved patient survival over the last decade. However, many patients either display primary (i.e., innate) or develop secondary (i.e., acquired) resistance to systemic treatments. Therapeutic resistance relies on the rewiring of multiple processes, including cancer metabolism, epigenetics, gene expression, and interactions with the tumor microenvironment that are only partially understood. Therefore, reliable biomarkers of resistance or response, capable of facilitating the choice of the best treatment option for each patient, are currently missing. Recently, activation of nicotinamide adenine dinucleotide (NAD) metabolism and, in particular, of its rate-limiting enzyme nicotinamide phosphoribosyltransferase (NAMPT) have been identified as key drivers of targeted therapy resistance and melanoma progression. Another major player in this context is the mammalian target of rapamycin (mTOR) pathway, which plays key roles in the regulation of melanoma cell anabolic functions and energy metabolism at the switch between sensitivity and resistance to targeted therapy. In this review, we summarize known resistance mechanisms to ICIs and targeted therapy, focusing on metabolic adaptation as one main mechanism of drug resistance. In particular, we highlight the roles of NAD/NAMPT and mTOR signaling axes in this context and overview data in support of their inhibition as a promising strategy to overcome treatment resistance.
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Loras A, Gil-Barrachina M, Marqués-Torrejón MÁ, Perez-Pastor G, Martinez-Cadenas C. UV-Induced Somatic Mutations Driving Clonal Evolution in Healthy Skin, Nevus, and Cutaneous Melanoma. Life (Basel) 2022; 12:life12091339. [PMID: 36143375 PMCID: PMC9503451 DOI: 10.3390/life12091339] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 08/17/2022] [Accepted: 08/26/2022] [Indexed: 11/24/2022] Open
Abstract
Introduction: Due to its aggressiveness, cutaneous melanoma (CM) is responsible for most skin cancer-related deaths worldwide. The origin of CM is closely linked to the appearance of UV-induced somatic mutations in melanocytes present in normal skin or in CM precursor lesions (nevi or dysplastic nevi). In recent years, new NGS studies performed on CM tissue have increased the understanding of the genetic somatic changes underlying melanomagenesis and CM tumor progression. Methods: We reviewed the literature using all important scientific databases. All articles related to genomic mutations in CM as well as normal skin and nevi were included, in particular those related to somatic mutations produced by UV radiation. Conclusions: CM development and progression are strongly associated with exposure to UV radiation, although each melanoma subtype has different characteristic genetic alterations and evolutionary trajectories. While BRAF and NRAS mutations are common in the early stages of tumor development for most CM subtypes, changes in CDKN2A, TP53 and PTEN, together with TERT promoter mutations, are especially common in advanced stages. Additionally, large genome duplications, loss of heterozygosity, and copy number variations are hallmarks of metastatic disease. Finally, the mutations driving melanoma targeted-therapy drug resistance are also summarized. The complete sequential stages of clonal evolution leading to CM onset from normal skin or nevi are still unknown, so further studies are needed in this field to shed light on the molecular pathways involved in CM malignant transformation and in melanoma acquired drug resistance.
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Affiliation(s)
- Alba Loras
- Department of Medicine, University of Valencia, 46010 Valencia, Spain
- Department of Medicine, Jaume I University of Castellon, 12071 Castellon, Spain
| | | | | | - Gemma Perez-Pastor
- Department of Dermatology, Valencia General University Hospital, 46014 Valencia, Spain
| | - Conrado Martinez-Cadenas
- Department of Medicine, Jaume I University of Castellon, 12071 Castellon, Spain
- Correspondence: ; Tel.: +34-964387607
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Shi C, Gu Z, Xu S, Ju H, Wu Y, Han Y, Li J, Li C, Wu J, Wang L, Li J, Zhou G, Ye W, Ren G, Zhang Z, Zhou R. Candidate therapeutic agents in a newly established triple wild-type mucosal melanoma cell line. Cancer Commun (Lond) 2022; 42:627-647. [PMID: 35666052 PMCID: PMC9257989 DOI: 10.1002/cac2.12315] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 03/03/2022] [Accepted: 05/23/2022] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Mucosal melanoma has characteristically distinct genetic features and typically poor prognosis. The lack of representative mucosal melanoma models, especially cell lines, has hindered translational research on this melanoma subtype. In this study, we aimed to establish and provide the biological properties, genomic features and the pharmacological profiles of a mucosal melanoma cell line that would contribute to the understanding and treatment optimization of molecularly-defined mucosal melanoma subtype. METHODS The sample was collected from a 67-year-old mucosal melanoma patient and processed into pieces for the establishment of cell line and patient-derived xenograft (PDX) model. The proliferation and tumorigenic property of cancer cells from different passages were evaluated, and whole-genome sequencing (WGS) was performed on the original tumor, PDX, established cell line, and the matched blood to confirm the establishment and define the genomic features of this cell line. AmpliconArchitect was conducted to depict the architecture of amplified regions detected by WGS. High-throughput drug screening (HTDS) assay including a total of 103 therapeutic agents was implemented on the established cell line, and selected candidate agents were validated in the corresponding PDX model. RESULTS A mucosal melanoma cell line, MM9H-1, was established which exhibited robust proliferation and tumorigenicity after more than 100 serial passages. Genomic analysis of MM9H-1, corresponding PDX, and the original tumor showed genetic fidelity across genomes, and MM9H-1 was defined as a triple wild-type (TWT) melanoma subtype lacking well-characterized "driver mutations". Instead, the amplification of several oncogenes, telomerase reverse transcriptase (TERT), v-Raf murine sarcoma viral oncogene homolog B1 (BRAF), melanocyte Inducing transcription factor (MITF) and INO80 complex ATPase subunit (INO80), via large-scale genomic rearrangement potentially contributed to oncogenesis of MM9H-1. Moreover, HTDS identified proteasome inhibitors, especially bortezomib, as promising therapeutic candidates for MM9H-1, which was verified in the corresponding PDX model in vivo. CONCLUSIONS We established and characterized a new mucosal melanoma cell line, MM9H-1, and defined this cell line as a TWT melanoma subtype lacking well-characterized "driver mutations". The MM9H-1 cell line could be adopted as a unique model for the preclinical investigation of mucosal melanoma.
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34
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Zhang H, Ma Y, Zhang Q, Liu R, Luo H, Wang X. A pancancer analysis of the carcinogenic role of receptor-interacting serine/threonine protein kinase-2 (RIPK2) in human tumours. BMC Med Genomics 2022; 15:97. [PMID: 35473583 PMCID: PMC9040268 DOI: 10.1186/s12920-022-01239-3] [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: 01/07/2022] [Accepted: 04/13/2022] [Indexed: 11/15/2022] Open
Abstract
Background To explore the expression and carcinogenic mechanism of RIPK2 in human tumours, and to provide the theoretical basis for the further study of RIPK2. Methods We used the TCGA, CPTAC, HPA databases to analyse the expression, mutation, and prognosis of RIPK2 in human tumours. Through the Cbioportal, Ualcan, TIMER2.0, and STRING websites, We understand the genetic variation, immune infiltration and enrichment analysis of RIPK2 related genes. Results RIPK2 was highly expressed in most tumours (such as BRCA, COAD and LUSC, etc.), and the high expression of RIPK2 was correlated with tumour stage and prognosis. In addition, Amplification was the main type of RIPK2 in tumour mutation state, and the amplification rate was about 8.5%. In addition, RIPK2 was positively associated with tumour-infiltrating immune cells (such as CD8+ T, Tregs, and cancer-associated fibroblasts). According to the KEGG analysis, RIPK2 may play a role in tumour mainly through NOD-like signaling pathway and NF-kappaB signaling pathway. GO enrichment analysis showed that the RIPK2 is mainly related to I-kappaB kinase/NF-kappaB signaling, Ribonucleoprotein granule and Ubiquitin-like protein ligase binding. Conclusion RIPK2 plays an important role in the occurrence, development and prognosis of malignant tumours. Our pancancer study provided a relatively comprehensive description of the carcinogenic effects of RIPK2 in different tumours, and provided useful information for further study of RIPK2. Supplementary Information The online version contains supplementary material available at 10.1186/s12920-022-01239-3.
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Affiliation(s)
- Hanqun Zhang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, People's Republic of China.,Department of Oncology, Guizhou Provincial People's Hospital, Guizhou, 550002, People's Republic of China
| | - Yan Ma
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, People's Republic of China
| | - Qiuning Zhang
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, People's Republic of China.,University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China.,Lanzhou Heavy Ion Hospital, Lanzhou, 730000, People's Republic of China
| | - Ruifeng Liu
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, People's Republic of China.,University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China.,Lanzhou Heavy Ion Hospital, Lanzhou, 730000, People's Republic of China
| | - Hongtao Luo
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, People's Republic of China.,University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China.,Lanzhou Heavy Ion Hospital, Lanzhou, 730000, People's Republic of China
| | - Xiaohu Wang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, People's Republic of China. .,Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, People's Republic of China. .,University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China. .,Lanzhou Heavy Ion Hospital, Lanzhou, 730000, People's Republic of China.
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35
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Torres-Ayuso P, Brognard J. Degraders: The Ultimate Weapon Against Amplified Driver Kinases in Cancer. Mol Pharmacol 2022; 101:191-200. [PMID: 35115411 PMCID: PMC9092480 DOI: 10.1124/molpharm.121.000306] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 01/27/2022] [Indexed: 12/02/2022] Open
Abstract
Amplification of pro-oncogenic kinases is a common genetic alteration driving tumorigenic phenotypes. Cancer cells rely on the amplified kinases to sustain cell proliferation, survival, and growth, presenting an opportunity to develop therapies targeting the amplified kinases. Utilizing small molecule catalytic inhibitors as therapies to target amplified kinases is plagued by de novo resistance driven by increased expression of the target, and amplified kinases can drive tumorigenic phenotypes independent of catalytic activity. Here, we discuss the emergence of proteolysis-targeting chimeras that provide an opportunity to target these oncogenic drivers effectively. SIGNIFICANCE STATEMENT: Protein kinases contribute to tumorigenesis through catalytic and noncatalytic mechanisms, and kinase gene amplifications are well described mechanisms of resistance to small molecule catalytic inhibitors. Repurposing catalytic inhibitors for the development of protein degraders will offer improved clinical benefits by targeting noncatalytic functions of kinases that promote tumorigenesis and overcoming resistance due to amplification.
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Affiliation(s)
- Pedro Torres-Ayuso
- Laboratory of Cell and Developmental Signaling, National Cancer Institute, Center for Cancer Research, Frederick, Maryland
| | - John Brognard
- Laboratory of Cell and Developmental Signaling, National Cancer Institute, Center for Cancer Research, Frederick, Maryland
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36
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Intermittent treatment of BRAF V600E melanoma cells delays resistance by adaptive resensitization to drug rechallenge. Proc Natl Acad Sci U S A 2022; 119:e2113535119. [PMID: 35290123 PMCID: PMC8944661 DOI: 10.1073/pnas.2113535119] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Preclinical studies of metastatic melanoma treated with targeted therapeutics have suggested that alternating periods of treatment and withdrawal might delay the onset of resistance. This has been attributed to drug addiction, where cells lose fitness upon drug removal due to the resulting hyperactivation of mitogen-activated protein (MAP) kinase signaling. This study presents evidence that the intermittent treatment response can also be explained by the resensitization of cells following drug removal and enhanced cell loss upon drug rechallenge. Resensitization is accompanied by adaptive transcriptomic switching and occurs despite the sustained expression of resistance genes throughout the intermittent treatment. Patients with melanoma receiving drugs targeting BRAFV600E and mitogen-activated protein (MAP) kinase kinases 1 and 2 (MEK1/2) invariably develop resistance and face continued progression. Based on preclinical studies, intermittent treatment involving alternating periods of drug withdrawal and rechallenge has been proposed as a method to delay the onset of resistance. The beneficial effect of intermittent treatment has been attributed to drug addiction, where drug withdrawal reduces the viability of resistant cells due to MAP kinase pathway hyperactivation. However, the mechanistic basis of the intermittent effect is incompletely understood. We show that intermittent treatment with the BRAFV600E inhibitor, LGX818/encorafenib, suppresses growth compared with continuous treatment in human melanoma cells engineered to express BRAFV600E, p61-BRAFV600E, or MEK2C125 oncogenes. Analysis of the BRAFV600E-overexpressing cells shows that, while drug addiction clearly occurs, it fails to account for the advantageous effect of intermittent treatment. Instead, growth suppression is best explained by resensitization during periods of drug removal, followed by cell death after drug readdition. Continuous treatment leads to transcriptional responses prominently associated with chemoresistance in melanoma. By contrast, cells treated intermittently reveal a subset of transcripts that reverse expression between successive cycles of drug removal and rechallenge and include mediators of cell invasiveness and the epithelial-to-mesenchymal transition. These transcripts change during periods of drug removal by adaptive switching, rather than selection pressure. Resensitization occurs against a background of sustained expression of melanoma resistance genes, producing a transcriptome distinct from that of the initial drug-naive cell state. We conclude that phenotypic plasticity leading to drug resensitization can underlie the beneficial effect of intermittent treatment.
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Sahil, Kaur K, Jaitak V. Thiazole and Related Heterocyclic Systems as Anticancer Agents: A Review on Synthetic Strategies, Mechanisms of Action and SAR Studies. Curr Med Chem 2022; 29:4958-5009. [DOI: 10.2174/0929867329666220318100019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 01/06/2022] [Accepted: 01/12/2022] [Indexed: 11/22/2022]
Abstract
Background:
Cancer is the second leading cause of death throughout the world. Many anticancer drugs are commercially available, but lack of selectivity, target specificity, cytotoxicity and development of resistance lead to serious side effects. There have been several experiments going on to develop compounds with minor or no side effects.
Objective:
This review mainly emphasizes synthetic strategies, SAR studies, and mechanism of action for thiazole, benzothiazole, and imidazothiazole containing compounds as anticancer agents.
Methods:
Recent literature related to thiazole and thiazole-related derivatives endowed with encouraging anticancer potential is reviewed. This review emphasizes contemporary strategies used for the synthesis of thiazole and related derivatives, mechanistic targets, and comprehensive structural activity relationship studies to provide perspective into the rational design of high-efficiency thiazole-based anticancer drug candidates.
Results:
Exhaustive literature survey indicated that thiazole derivatives are associated with properties of inducing
apoptosis and disturbing tubulin assembly. Thiazoles are also associated with the inhibition of NFkB/mTOR/PI3K/AkT and regulation of estrogen-mediated activity. Furthermore, thiazole derivatives have been found to modulate critical targets such as topoisomerase and HDAC.
Conclusion:
Thiazole derivatives seem to be quite competent and act through various mechanisms. Some of the thiazole derivatives, such as compounds 29, 40, 62, and 74a with IC50 values of 0.05 μM, 0.00042 μM, 0.18 μM, and 0.67 μM, respectively not only have anticancer activity but they also have lower toxicity and better absorption. Therefore, some other similar compounds could be investigated to aid in the development of anticancer pharmacophores.
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Affiliation(s)
- Sahil
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda (Pb.), India
| | - Kamalpreet Kaur
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda (Pb.), India
| | - Vikas Jaitak
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda (Pb.), India
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Chen J, Li G, Qin P, Chen J, Ye N, Waddington JL, Zhen X. Allosteric Modulation of the Sigma-1 Receptor Elicits Antipsychotic-like Effects. Schizophr Bull 2022; 48:474-484. [PMID: 34865170 PMCID: PMC8886599 DOI: 10.1093/schbul/sbab137] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Allosteric modulation represents an important approach in drug discovery because of its advantages in safety and selectivity. SOMCL-668 is the first selective and potent sigma-1 receptor allosteric modulator, discovered in our laboratory. The present work investigates the potential therapeutic effects of SOMCL-668 on phencyclidine (PCP)-induced schizophrenia-related behavior in mice and further elucidates underlying mechanisms for its antipsychotic-like effects. SOMCL-668 not only attenuated acute PCP-induced hyperactivity and PPI disruption, but also ameliorated social deficits and cognitive impairment induced by chronic PCP treatment. Pretreatment with the selective sigma-1 receptor antagonist BD1047 blocked the effects of SOMCL-668, indicating sigma-1 receptor-mediated responses. This was confirmed using sigma-1 receptor knockout mice, in which SOMCL-668 failed to ameliorate PPI disruption and hyperactivity induced by acute PCP and social deficits and cognitive impairment induced by chronic PCP treatment. Additionally, in vitro SOMCL-668 exerted positive modulation of sigma-1 receptor agonist-induced intrinsic plasticity in brain slices recorded by patch-clamp. Furthermore, in vivo lower dose of SOMCL-668 exerted positive modulation of improvement in social deficits and cognitive impairment induced by the selective sigma-1 agonist PRE084. Also, SOMCL-668 reversed chronic PCP-induced down-regulation in expression of frontal cortical p-AKT/AKT, p-CREB/CREB and BDNF in wide-type but not sigma-1 knockout mice. Moreover, administration of the PI3K/AKT inhibitor LY294002 abolished amelioration by SOMCL-668 of chronic PCP-induced schizophrenia-related behaviors by inhibition of BDNF expression. The present data provide initial, proof-of-concept evidence that allosteric modulation of the sigma-1 receptor may be a novel approach for the treatment of psychotic illness.
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Affiliation(s)
- Jiali Chen
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Guangying Li
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Pingping Qin
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Jiaojiao Chen
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Na Ye
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - John L Waddington
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
- School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Xuechu Zhen
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
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Ros J, Saoudi N, Salvà F, Baraibar I, Alonso G, Tabernero J, Elez E. Ongoing and evolving clinical trials enhancing future colorectal cancer treatment strategies. Expert Opin Investig Drugs 2022; 31:235-247. [PMID: 35133234 DOI: 10.1080/13543784.2022.2040016] [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] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Molecular profiling has led to significantly longer survival in metastatic colorectal cancer (CRC) patients. Clinical guidelines recommend testing for KRAS/NRAS, BRAF and MSI status and over the last few years several promising new biomarkers have also been identified. Circulating tumor DNA has reshaped the prognosis of localized CRC. These genomic findings can guide treatment management to improve clinical outcomes. AREAS COVERED Preclinical and clinical data over the last decade were reviewed for known and novel biomarkers with clinical implications in refractory and metastatic CRC. In the localized stage, al clinical trials involving new approaches such as liquid biopsy or neoadjuvant immunotherapy are also discussed. Molecular alterations and targeted agents are described, and data from completed and ongoing studies with targeted therapy and immunotherapies are presented. EXPERT OPINION The implementation of liquid biopsies in the localized CRC setting has reshaped management of this disease. The expanded use of biomarkers to guide the treatment of patients with CRC has revealed a level of complexity arising from interactions between different biomarkers. Prevalence of most established targetable biomarkers is low, however the number of identified biomarkers in CRC is increasing. Thus, metastatic CRC may ultimately be considered an umbrella diagnosis encompassing numerous rare disease subtypes.
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Affiliation(s)
- Javier Ros
- Medical Oncology, Vall d'Hebron University Hospital and Vall D'Hebron Institute of Oncology (VHIO), Barcelona, Spain.,Department of Precision Medicine, Medical Oncology, Università Degli Studi Della Campania Luigi Vanvitelli, Naples, Campania, Italy
| | - Nadia Saoudi
- Medical Oncology, Vall d'Hebron University Hospital and Vall D'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Francesc Salvà
- Medical Oncology, Vall d'Hebron University Hospital and Vall D'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Iosune Baraibar
- Medical Oncology, Vall d'Hebron University Hospital and Vall D'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Guzman Alonso
- Medical Oncology, Vall d'Hebron University Hospital and Vall D'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Josep Tabernero
- Medical Oncology, Vall d'Hebron University Hospital and Vall D'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Elena Elez
- Medical Oncology, Vall d'Hebron University Hospital and Vall D'Hebron Institute of Oncology (VHIO), Barcelona, Spain
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Campbell MR, Ruiz-Saenz A, Peterson E, Agnew C, Ayaz P, Garfinkle S, Littlefield P, Steri V, Oeffinger J, Sampang M, Shan Y, Shaw DE, Jura N, Moasser MM. Targetable HER3 functions driving tumorigenic signaling in HER2-amplified cancers. Cell Rep 2022; 38:110291. [PMID: 35108525 PMCID: PMC8889928 DOI: 10.1016/j.celrep.2021.110291] [Citation(s) in RCA: 7] [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: 10/12/2020] [Revised: 08/30/2021] [Accepted: 12/29/2021] [Indexed: 12/26/2022] Open
Abstract
Effective inactivation of the HER2-HER3 tumor driver has remained elusive because of the challenging attributes of the pseudokinase HER3. We report a structure-function study of constitutive HER2-HER3 signaling to identify opportunities for targeting. The allosteric activation of the HER2 kinase domain (KD) by the HER3 KD is required for tumorigenic signaling and can potentially be targeted by allosteric inhibitors. ATP binding within the catalytically inactive HER3 KD provides structural rigidity that is important for signaling, but this is mimicked, not opposed, by small molecule ATP analogs, reported here in a bosutinib-bound crystal structure. Mutational disruption of ATP binding and molecular dynamics simulation of the apo KD of HER3 identify a conformational coupling of the ATP pocket with a hydrophobic AP-2 pocket, analogous to EGFR, that is critical for tumorigenic signaling and feasible for targeting. The value of these potential target sites is confirmed in tumor growth assays using gene replacement techniques.
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Affiliation(s)
- Marcia R Campbell
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Ana Ruiz-Saenz
- Departments of Cell Biology & Medical Oncology, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Elliott Peterson
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Christopher Agnew
- Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Pelin Ayaz
- D. E. Shaw Research, New York, NY 10036, USA
| | | | - Peter Littlefield
- Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Veronica Steri
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Julie Oeffinger
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Maryjo Sampang
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Yibing Shan
- D. E. Shaw Research, New York, NY 10036, USA
| | - David E Shaw
- D. E. Shaw Research, New York, NY 10036, USA; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA
| | - Natalia Jura
- Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Mark M Moasser
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
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41
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Whale AJ, King M, Hull RM, Krueger F, Houseley J. Stimulation of adaptive gene amplification by origin firing under replication fork constraint. Nucleic Acids Res 2022; 50:915-936. [PMID: 35018465 PMCID: PMC8789084 DOI: 10.1093/nar/gkab1257] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 11/26/2021] [Accepted: 12/06/2021] [Indexed: 02/06/2023] Open
Abstract
Adaptive mutations can cause drug resistance in cancers and pathogens, and increase the tolerance of agricultural pests and diseases to chemical treatment. When and how adaptive mutations form is often hard to discern, but we have shown that adaptive copy number amplification of the copper resistance gene CUP1 occurs in response to environmental copper due to CUP1 transcriptional activation. Here we dissect the mechanism by which CUP1 transcription in budding yeast stimulates copy number variation (CNV). We show that transcriptionally stimulated CNV requires TREX-2 and Mediator, such that cells lacking TREX-2 or Mediator respond normally to copper but cannot acquire increased resistance. Mediator and TREX-2 can cause replication stress by tethering transcribed loci to nuclear pores, a process known as gene gating, and transcription at the CUP1 locus causes a TREX-2-dependent accumulation of replication forks indicative of replication fork stalling. TREX-2-dependent CUP1 gene amplification occurs by a Rad52 and Rad51-mediated homologous recombination mechanism that is enhanced by histone H3K56 acetylation and repressed by Pol32 and Pif1. CUP1 amplification is also critically dependent on late-firing replication origins present in the CUP1 repeats, and mutations that remove or inactivate these origins strongly suppress the acquisition of copper resistance. We propose that replicative stress imposed by nuclear pore association causes replication bubbles from these origins to collapse soon after activation, leaving a tract of H3K56-acetylated chromatin that promotes secondary recombination events during elongation after replication fork re-start events. The capacity for inefficient replication origins to promote copy number variation renders certain genomic regions more fragile than others, and therefore more likely to undergo adaptive evolution through de novo gene amplification.
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Affiliation(s)
- Alex J Whale
- Epigenetics Programme, Babraham Institute, Cambridge, UK
| | - Michelle King
- Epigenetics Programme, Babraham Institute, Cambridge, UK
| | - Ryan M Hull
- Epigenetics Programme, Babraham Institute, Cambridge, UK
| | - Felix Krueger
- Babraham Bioinformatics, Babraham Institute, Cambridge, UK
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Zhi J, Yi J, Hou X, Wang W, Yang W, Hu L, Huang J, Guo S, Ruan X, Gao M, Zheng X. Targeting SHP2 sensitizes differentiated thyroid carcinoma to the MEK inhibitor. Am J Cancer Res 2022; 12:247-264. [PMID: 35141016 PMCID: PMC8822290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Accepted: 11/30/2021] [Indexed: 06/14/2023] Open
Abstract
Pharmacologic targeting of components of the MAPK/ERK pathway in differentiated thyroid carcinoma (DTC) is often limited due to the development of adaptive resistance. However, the detailed mechanism of MEK inhibitor (MEKi) resistance is not fully understood. Here, MEKi-resistant models were constructed successfully, in which multiple receptor tyrosine kinases (RTKs) signaling pathways and Src-homology 2 domain-containing phosphatase 2 (SHP2) were activated in MEKi-resistant cells. Given the physiological role of SHP2 as the downstream target of many RTKs, we first found blockade of SHP2 enhanced the sensitivity to MEKi in constructed MEKi-resistant models. Interestingly, we also found that compared with MEKi treatment alone, MEKi in combination with an SHP2 inhibitor markedly suppressed the reactivation of the MEK/ERK pathway; thus, the addition of the SHP2 inhibitor significantly improved the antitumor effects of MEKi. The synergistic suppression of DTC upon treatment with both inhibitors was further confirmed in xenograft models and transgenic models. Thus, our data suggest that RTKs activation leads to reactivation of the MAPK pathway and resistance to MEKi in DTC, which is reversed by SHP2 blockade. As a novel active inhibitor of SHP2, SHP099 in combination with MEKi is a promising therapeutic approach for advanced DTC and MEKi-resistant one.
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Affiliation(s)
- Jingtai Zhi
- Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for CancerTianjin 300060, People’s Republic of China
- Department of Otolaryngology-Head and Neck Surgery, Tianjin First Center Hospital, Nankai District of Tianjin, Institute of Otolaryngology of Tianjin, Key Laboratory of Auditory Speech and Balance Medicine, Key Clinical Discipline of Tianjin (Otolaryngology), Otolaryngology Clinical Quality Control CentreRehabilitation Road No. 24, Tianjin 300192, People’s Republic of China
| | - Jiaoyu Yi
- Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for CancerTianjin 300060, People’s Republic of China
| | - Xiukun Hou
- Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for CancerTianjin 300060, People’s Republic of China
| | - Wei Wang
- Department of Otolaryngology-Head and Neck Surgery, Tianjin First Center Hospital, Nankai District of Tianjin, Institute of Otolaryngology of Tianjin, Key Laboratory of Auditory Speech and Balance Medicine, Key Clinical Discipline of Tianjin (Otolaryngology), Otolaryngology Clinical Quality Control CentreRehabilitation Road No. 24, Tianjin 300192, People’s Republic of China
| | - Weiwei Yang
- Department of Otolaryngology-Head and Neck Surgery, Tianjin First Center Hospital, Nankai District of Tianjin, Institute of Otolaryngology of Tianjin, Key Laboratory of Auditory Speech and Balance Medicine, Key Clinical Discipline of Tianjin (Otolaryngology), Otolaryngology Clinical Quality Control CentreRehabilitation Road No. 24, Tianjin 300192, People’s Republic of China
| | - Linfei Hu
- Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for CancerTianjin 300060, People’s Republic of China
| | - Jianfeng Huang
- Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute10901 North, Torrey Pines Road, La Jolla, CA 92037, USA
| | - Shicheng Guo
- Department of Medical Genetics, School of Medicine and Public Health, University of Wisconsin-MadisonMadison, WI 53705, USA
- Center for Precision Medicine Research, Marshfield Clinic Research InstituteMarshfield, WI 54449, USA
| | - Xianhui Ruan
- Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for CancerTianjin 300060, People’s Republic of China
| | - Ming Gao
- Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for CancerTianjin 300060, People’s Republic of China
- Department of Thyroid and Breast Surgery, Tianjin Union Medical CenterNo. 190 Jieyuan Road, Hongqiao District, Tianjin 300121, People’s Republic of China
| | - Xiangqian Zheng
- Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for CancerTianjin 300060, People’s Republic of China
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Ali EMH, Mersal KI, Ammar UM, Zaraei SO, Abdel-Maksoud MS, El-Gamal MI, Haque MM, Das T, Kim EE, Lee JS, Lee KH, Kim HK, Oh CH. Structural optimization of 4-(imidazol-5-yl)pyridine derivatives affords broad-spectrum anticancer agents with selective B-RAF V600E/p38α kinase inhibitory activity: Synthesis, in vitro assays and in silico study. Eur J Pharm Sci 2022; 171:106115. [PMID: 34995782 DOI: 10.1016/j.ejps.2022.106115] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 11/26/2021] [Accepted: 12/17/2021] [Indexed: 01/10/2023]
Abstract
In the current article, we introduce design of a new series of 4-(imidazol-5-yl)pyridines with improved anticancer activity and selective B-RAFV600E/p38α kinase inhibitory activity. Based on a previous work, a group of structural modifications were applied affording the new potential antiproliferative agents. Towards extensive biological assessment of the target compounds, an in vitro anticancer assay was conducted over NCI 60-cancer cell lines panel representing blood, lung, colon, CNS, skin, ovary, renal, prostate, and breast cancers. Compounds 7c, 7d, 8b, 9b, 9c, 10c, 10d, and 11b exhibited the highest potency among the tested compounds and demonstrated sub-micromolar or one-digit micromolar GI50 values against the majority of the employed cell lines. Compound 10c emerged as the most potent agent with nano-molar activity over most of the cells and incredible activity against melanoma (MDA-MB-435) cell line (GI50 70 nM). It is much more potent than sorafenib, the clinically used anticancer drug, against almost all the NCI-60 cell lines. Further cell-based mechanistic assays showed that compound 10c induced cell cycle arrest and promoted apoptosis in K562, MCF-7 and HT29 cancer cell lines. In addition, compound 10c induced autophagy in the three cancer cell lines. Kinase profiling of 10c showed its inhibitory effects and selectivity towards B-RAFV600E and p38α kinases with IC50 values of 1.84 and 0.726 µM, respectively. Docking of compound 10c disclosed its high affinity in the kinases pockets. Compound 10c represent a promising anticancer agent, that could be optimized in order to improve its kinase activity aiming at developing potential anticancer agents. The conformational stability of compound 10c in the active site of B-RAFV600E and p38α kinases was studied by applying molecular dynamic simulation of the compound in the two kinases for 600 ns in comparison to the native ligands.
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Affiliation(s)
- Eslam M H Ali
- Center of Biomaterials, Korea Institute of Science & Technology (KIST School), Seoul, Seongbuk-gu, 02792, Republic of Korea; University of Science & Technology (UST), Daejeon, Yuseong-gu, 34113, Republic of Korea; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo, 12055, Egypt
| | - Karim I Mersal
- Center of Biomaterials, Korea Institute of Science & Technology (KIST School), Seoul, Seongbuk-gu, 02792, Republic of Korea; University of Science & Technology (UST), Daejeon, Yuseong-gu, 34113, Republic of Korea; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo, 12055, Egypt
| | - Usama M Ammar
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0NR, Scotland, United Kingdom
| | - Seyed-Omar Zaraei
- Center of Biomaterials, Korea Institute of Science & Technology (KIST School), Seoul, Seongbuk-gu, 02792, Republic of Korea; University of Science & Technology (UST), Daejeon, Yuseong-gu, 34113, Republic of Korea
| | - Mohammed S Abdel-Maksoud
- Medicinal & Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre NRC (ID: 60014618)), Dokki, Giza, 12622, Egypt
| | - Mohammed I El-Gamal
- Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates; Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Md Mamunul Haque
- Department of Pharmacology, College of Medicine, Korea University, Seoul 02841, Republic of Korea
| | - Tanuza Das
- Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
| | - Eunice EunKyeong Kim
- Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
| | - Jun-Seok Lee
- Department of Pharmacology, College of Medicine, Korea University, Seoul 02841, Republic of Korea
| | - Kwan Hyi Lee
- Center of Biomaterials, Korea Institute of Science & Technology (KIST School), Seoul, Seongbuk-gu, 02792, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea
| | - Hee-Kwon Kim
- Department of Nuclear Medicine, Molecular Imaging & Therapeutic Medicine Research Center, Jeonbuk National University Medical School and Hospital, 20 Geonji-ro, Deokjin-gu, Jeonju 54907, Republic of Korea; Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, 20 Geonji-ro, Deokjin-gu, Jeonju 54907, Republic of Korea.
| | - Chang-Hyun Oh
- Center of Biomaterials, Korea Institute of Science & Technology (KIST School), Seoul, Seongbuk-gu, 02792, Republic of Korea; University of Science & Technology (UST), Daejeon, Yuseong-gu, 34113, Republic of Korea.
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BRAF mutation in colorectal cancer: An update. ARCHIVE OF ONCOLOGY 2022. [DOI: 10.2298/aoo220130004c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Colon cancer is a leading cause of cancer-related deaths worldwide. About 10%
of all colon cancer patients are found to have a mutation in BRAF
proto-oncogene that arise as a result of a substitution of amino acid valine
with glutamate at position 600 (V600E). This specific mutation is also found
in melanomas, but at even higher percent - in up to 60% of patients. A
particular category of drugs called BRAF inhibitors, have been developed in
order to increase survival. But, while in patients with melanoma this class
of drugs work well especially when combined with mitogen-activated protein
kinase inhibitors, they have low efficacy in patients with metastatic
colorectal cancer suggesting different mechanism of action and development
of drug resistance. This review summarise recent findings aimed to highlight
events in BRAF mutations in metastatic colorectal cancer.
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45
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Hou P, Wang YA. Conquering oncogenic KRAS and its bypass mechanisms. Theranostics 2022; 12:5691-5709. [PMID: 35966590 PMCID: PMC9373815 DOI: 10.7150/thno.71260] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 05/05/2022] [Indexed: 11/19/2022] Open
Abstract
Aberrant activation of KRAS signaling is common in cancer, which has catalyzed heroic drug development efforts to target KRAS directly or its downstream signaling effectors. Recent works have yielded novel small molecule drugs with promising preclinical and clinical activities. Yet, no matter how a cancer is addicted to a specific target - cancer's genetic and biological plasticity fashions a variety of resistance mechanisms as a fait accompli, limiting clinical benefit of targeted interventions. Knowledge of these mechanisms may inform combination strategies to attack both oncogenic KRAS and subsequent bypass mechanisms.
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Affiliation(s)
- Pingping Hou
- Center for Cell Signaling, Rutgers New Jersey Medical School, Newark, New Jersey 07103, USA.,Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, Newark, New Jersey 07103, USA.,Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.,Lead contact
| | - Y Alan Wang
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
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46
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Nell RJ, Zoutman WH, Calbet-Llopart N, Garcia AP, Menger NV, Versluis M, Puig S, Gruis NA, van der Velden PA. Accurate Quantification of T Cells in Copy Number Stable and Unstable DNA Samples Using Multiplex Digital PCR. J Mol Diagn 2021; 24:88-100. [PMID: 34775028 DOI: 10.1016/j.jmoldx.2021.10.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 10/06/2021] [Accepted: 10/13/2021] [Indexed: 11/25/2022] Open
Abstract
An accurate T-cell quantification is prognostically and therapeutically relevant in various malignancies. We previously developed a digital PCR-based approach offering a precise T-cell enumeration in small amounts of DNA. However, it may be challenging to apply this method in malignant specimens, as copy number instability can disturb the underlying mathematical model. For example, approximately 24% of the tumors from The Cancer Genome Atlas pan-cancer data set carried a copy number alteration affecting our TRB gene T-cell marker, which would cause an underestimation or overestimation of the T-cell fraction. In this study, we introduce a multiplex digital PCR experimental setup to quantify T cells in copy number unstable DNA samples. By implementing a so-called regional corrector, genetic alterations involving the T-cell marker locus can be recognized and corrected for. This novel setup is evaluated mathematically in silico and validated in vitro by measuring T-cell presence in various samples with a known T-cell fraction. The utility of the approach is further demonstrated in copy number altered cutaneous melanomas. Our novel multiplex setup provides a simple, but accurate, DNA-based T-cell quantification in both copy number stable and unstable specimens. This approach has potential clinical and diagnostic applications, as it does not depend on availability of T-cell epitopes, has low requirements for sample quantity and quality, and can be performed in a relatively easy experiment.
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Affiliation(s)
- Rogier J Nell
- Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands
| | - Willem H Zoutman
- Department of Dermatology, Leiden University Medical Center, Leiden, the Netherlands
| | - Neus Calbet-Llopart
- Department of Dermatology, Hospital Clínic de Barcelona, IDIBAPS, University of Barcelona, Centro Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Barcelona, Spain
| | - Adriana P Garcia
- Department of Pathology, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Nino V Menger
- Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands
| | - Mieke Versluis
- Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands
| | - Susana Puig
- Department of Dermatology, Hospital Clínic de Barcelona, IDIBAPS, University of Barcelona, Centro Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Barcelona, Spain
| | - Nelleke A Gruis
- Department of Dermatology, Leiden University Medical Center, Leiden, the Netherlands
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Thongchot S, Jamjuntra P, Prasopsiri J, Thuwajit P, Sawasdee N, Poungvarin N, Warnnissorn M, Sa-Nguanraksa D, O-Charoenrat P, Yenchitsomanus PT, Thuwajit C. Establishment and characterization of novel highly aggressive HER2‑positive and triple‑negative breast cancer cell lines. Oncol Rep 2021; 46:254. [PMID: 34651665 PMCID: PMC8548790 DOI: 10.3892/or.2021.8205] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 09/16/2021] [Indexed: 11/05/2022] Open
Abstract
Breast cancer cell lines are widely used as an in vitro system with which to study the mechanisms underlying biological and chemotherapeutic resistance. In the present study, two novel breast cancer cell lines designated as PC‑B‑142CA and PC‑B‑148CA were successfully established from HER2‑positive and triple‑negative (TN) breast cancer tissues. The cell lines were characterized by cytokeratin (CK), α‑smooth muscle actin (α‑SMA), fibroblast‑activation protein (FAP) and programmed death‑ligand 1 (PD‑L1). Cell proliferation was assessed using a colony formation assay, an MTS assay, 3‑dimensional (3‑D) spheroid and 3‑D organoid models. Wound healing and Transwell migration assays were used to explore the cell migration capability. The responses to doxorubicin (DOX) and paclitaxel (PTX) were evaluated by 3‑D spheroids. The results showed that the PC‑B‑142CA and PC‑B‑148CA cell lines were α‑SMA‑negative, FAP‑negative, CK‑positive and PD‑L1‑positive. Both cell lines were adherent with the ability of 3‑D‑multicellular spheroid and organoid formations; invadopodia were found in the spheroids/organoids of only PC‑B‑148CA. PC‑B‑142CA had a faster proliferative but lower metastatic rate compared to PC‑B‑148CA. Compared to MDA‑MB‑231, a commercial TN breast cancer cell line, PC‑B‑148CA had a similar CD44+/CD24‑ stemness property (96.90%), whereas only 8.75% were found in PC‑B‑142CA. The mutations of BRCA1/2, KIT, PIK3CA, SMAD4, and TP53 were found in PC‑B‑142CA cells related to the resistance of several drugs, whereas PC‑B‑148CA had mutated BRCA2, NRAS and TP53. In conclusion, PC‑B‑142CA can serve as a novel HER2‑positive breast cancer cell line for drug resistance studies; while PC‑B‑148CA is a novel TN breast cancer cell line suitable for metastatic and stemness‑related properties.
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Affiliation(s)
- Suyanee Thongchot
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Pranisa Jamjuntra
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Jaturawitt Prasopsiri
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Peti Thuwajit
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Nunghathai Sawasdee
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Naravat Poungvarin
- Department of Clinical Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Malee Warnnissorn
- Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Doonyapat Sa-Nguanraksa
- Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | | | - Pa-Thai Yenchitsomanus
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Chanitra Thuwajit
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
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48
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Wang B, Zhang W, Zhang G, Kwong L, Lu H, Tan J, Sadek N, Xiao M, Zhang J, Labrie M, Randell S, Beroard A, Sugarman E, Rebecca VW, Wei Z, Lu Y, Mills GB, Field J, Villanueva J, Xu X, Herlyn M, Guo W. Targeting mTOR signaling overcomes acquired resistance to combined BRAF and MEK inhibition in BRAF-mutant melanoma. Oncogene 2021; 40:5590-5599. [PMID: 34304249 PMCID: PMC8445818 DOI: 10.1038/s41388-021-01911-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 06/14/2021] [Accepted: 06/17/2021] [Indexed: 12/30/2022]
Abstract
Targeting MAPK pathway using a combination of BRAF and MEK inhibitors is an efficient strategy to treat melanoma harboring BRAF-mutation. The development of acquired resistance is inevitable due to the signaling pathway rewiring. Combining western blotting, immunohistochemistry, and reverse phase protein array (RPPA), we aim to understanding the role of the mTORC1 signaling pathway, a center node of intracellular signaling network, in mediating drug resistance of BRAF-mutant melanoma to the combination of BRAF inhibitor (BRAFi) and MEK inhibitor (MEKi) therapy. The mTORC1 signaling pathway is initially suppressed by BRAFi and MEKi combination in melanoma but rebounds overtime after tumors acquire resistance to the combination therapy (CR) as assayed in cultured cells and PDX models. In vitro experiments showed that a subset of CR melanoma cells was sensitive to mTORC1 inhibition. The mTOR inhibitors, rapamycin and NVP-BEZ235, induced cell cycle arrest and apoptosis in CR cell lines. As a proof-of-principle, we demonstrated that rapamycin and NVP-BEZ235 treatment reduced tumor growth in CR xenograft models. Mechanistically, AKT or ERK contributes to the activation of mTORC1 in CR cells, depending on PTEN status of these cells. Our study reveals that mTOR activation is essential for drug resistance of melanoma to MAPK inhibitors, and provides insight into the rewiring of the signaling networks in CR melanoma.
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Affiliation(s)
- Beike Wang
- Department of Biology, School of Arts & Sciences, University of Pennsylvania, Philadelphia, PA, USA
| | - Wei Zhang
- Department of Biology, School of Arts & Sciences, University of Pennsylvania, Philadelphia, PA, USA
| | - Gao Zhang
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA
- Department of Neurosurgery, The Preston Robert Tisch Brain Tumor Center and Department of Pathology, Duke University Medical Center, Durham, NC, USA
| | - Lawrence Kwong
- Department of Translation Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hezhe Lu
- Center for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - Jiufeng Tan
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA
| | - Norah Sadek
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA
| | - Min Xiao
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA
| | - Jie Zhang
- Department of Computer Science, New Jersey Institute of Technology, Newark, NJ, USA
| | - Marilyne Labrie
- Department of Cell, Developmental and Cancer Biology, School of Medicine, and Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Sergio Randell
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA
| | - Aurelie Beroard
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA
| | - Eric Sugarman
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA
| | - Vito W Rebecca
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA
| | - Zhi Wei
- Department of Computer Science, New Jersey Institute of Technology, Newark, NJ, USA
| | - Yiling Lu
- Department of Genomic Medicine, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Gordon B Mills
- Department of Cell, Developmental and Cancer Biology, School of Medicine, and Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Jeffrey Field
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Jessie Villanueva
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA
| | - Xiaowei Xu
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Meenhard Herlyn
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
| | - Wei Guo
- Department of Biology, School of Arts & Sciences, University of Pennsylvania, Philadelphia, PA, USA.
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Beech C, Hechtman JF. Molecular Approach to Colorectal Carcinoma: Current Evidence and Clinical Application. Surg Pathol Clin 2021; 14:429-441. [PMID: 34373094 DOI: 10.1016/j.path.2021.05.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Colorectal carcinoma is one of the most common cancer types in men and women, responsible for both the third highest incidence of new cancer cases and the third highest cause of cancer deaths. In the last several decades, the molecular mechanisms surrounding colorectal carcinoma's tumorigenesis have become clearer through research, providing new avenues for diagnostic testing and novel approaches to therapeutics. Laboratories are tasked with providing the most current information to help guide clinical decisions. In this review, we summarize the current knowledge surrounding colorectal carcinoma tumorigenesis and highlight clinically relevant molecular testing.
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Affiliation(s)
- Cameron Beech
- Department of Pathology, Yale New Haven Hospital, New Haven, CT, USA
| | - Jaclyn F Hechtman
- Molecular and GI Pathologist, NeoGenomics Laboratories, Fort Myers, FL, USA.
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50
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Precision oncology in metastatic colorectal cancer - from biology to medicine. Nat Rev Clin Oncol 2021; 18:506-525. [PMID: 33864051 DOI: 10.1038/s41571-021-00495-z] [Citation(s) in RCA: 141] [Impact Index Per Article: 35.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/01/2021] [Indexed: 02/06/2023]
Abstract
Remarkable progress has been made in the development of biomarker-driven targeted therapies for patients with multiple cancer types, including melanoma, breast and lung tumours, although precision oncology for patients with colorectal cancer (CRC) continues to lag behind. Nonetheless, the availability of patient-derived CRC models coupled with in vitro and in vivo pharmacological and functional analyses over the past decade has finally led to advances in the field. Gene-specific alterations are not the only determinants that can successfully direct the use of targeted therapy. Indeed, successful inhibition of BRAF or KRAS in metastatic CRCs driven by activating mutations in these genes requires combinations of drugs that inhibit the mutant protein while at the same time restraining adaptive resistance via CRC-specific EGFR-mediated feedback loops. The emerging paradigm is, therefore, that the intrinsic biology of CRC cells must be considered alongside the molecular profiles of individual tumours in order to successfully personalize treatment. In this Review, we outline how preclinical studies based on patient-derived models have informed the design of practice-changing clinical trials. The integration of these experiences into a common framework will reshape the future design of biology-informed clinical trials in this field.
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