CRISPR Screens Identify Essential Cell Growth Mediators in BRAF-inhibitor Resistant Melanoma
CRISPR Screens Identify Essential Cell Growth Mediators in BRAF-inhibitor Resistant Melanoma
Abstract BRAF is a serine-threonine kinase that harbors activating mutations in ～7% of human malignancies and ～60% of melanomas. Despite initial clinical responses to BRAF inhibitors (BRAFi), patients frequently develop drug resistance. To identify candidate therapeutic targets for BRAFi-resistant melanoma, we conducted CRISPR screens in melanoma cells harboring an activating BRAF mutation that had also acquired resistance to BRAFi. The screens identified pathways and genes critical for BRAFi resistance in melanoma cells. To investigate the mechanisms and pathways enabling resistance to BRAFi in melanomas, we integrated expression data, ATAC-seq, and CRISPR screen results. We identified the JUN family of transcription factors and the ETS family transcription factor ETV5 as key regulators of CDK6 that enabled resistance to BRAFi in melanoma cells. Our findings reveal genes whose loss of function conferred resistance to a selective BRAF inhibitor, providing new insight into signaling pathways that contribute to acquired resistance in melanoma.
Han Tong、Traugh Nicole、Liu Hailing、Liu Yin、Brown Myles、Chen Chen-Hao、Li Ziyi、Gu Shengqing、Shi Sailing、Xiao Tengfei、Wang Binbin、Jiang Peng、Boland Genevieve M.、Liu X. Shirley、Wu Qiu、Wang Xiaoqing、Sahu Avinash
Clinical Translational Research Center, Shanghai Pulmonary Hospital, School of Life Sciences and Technology, Tongji UniversityDepartment of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical SchoolClinical Translational Research Center, Shanghai Pulmonary Hospital, School of Life Sciences and Technology, Tongji UniversityDepartment of Clinical Laboratory, Shanghai Pulmonary Hospital, Tongji University School of MedicineDepartment of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School||Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public HealthDepartment of Data Sciences, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public HealthClinical Translational Research Center, Shanghai Pulmonary Hospital, School of Life Sciences and Technology, Tongji University||Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical SchoolDepartment of Data Sciences, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public HealthClinical Translational Research Center, Shanghai Pulmonary Hospital, School of Life Sciences and Technology, Tongji UniversityDepartment of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical SchoolClinical Translational Research Center, Shanghai Pulmonary Hospital, School of Life Sciences and Technology, Tongji University||Department of Data Sciences, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public HealthDepartment of Data Sciences, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public HealthCenter for Cancer Research, Massachusetts General Hospital, Harvard Medical School||Department of Surgery, Massachusetts General Hospital, Harvard Medical SchoolDepartment of Data Sciences, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public Health||Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public HealthClinical Translational Research Center, Shanghai Pulmonary Hospital, School of Life Sciences and Technology, Tongji UniversityDepartment of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical SchoolDepartment of Data Sciences, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public Health
医药卫生理论医学研究方法肿瘤学
Drug resistanceCRISPR screenMelanomaBRAF inhibitorGene regulation
Han Tong,Traugh Nicole,Liu Hailing,Liu Yin,Brown Myles,Chen Chen-Hao,Li Ziyi,Gu Shengqing,Shi Sailing,Xiao Tengfei,Wang Binbin,Jiang Peng,Boland Genevieve M.,Liu X. Shirley,Wu Qiu,Wang Xiaoqing,Sahu Avinash.CRISPR Screens Identify Essential Cell Growth Mediators in BRAF-inhibitor Resistant Melanoma[EB/OL].(2025-03-28)[2025-05-05].https://www.biorxiv.org/content/10.1101/2019.12.16.876631.点此复制
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