Journal
GENOMICS PROTEOMICS & BIOINFORMATICS
Volume 18, Issue 1, Pages 26-40Publisher
ELSEVIER
DOI: 10.1016/j.gpb.2020.02.002
Keywords
Drug resistance; CRISPR screen; Melanoma; BRAF inhibitor; Gene regulation
Categories
Funding
- National Natural Science Foundation of China [81872290]
- National Key R&D Program of China [2017YFC0908500]
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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, patients frequently develop drug resistance. To identify candidate therapeutic targets for BRAF inhi-bitor resistant melanoma, we conduct CRISPR screens in melanoma cells harboring an activating BRAF mutation that had also acquired resistance to BRAF inhibitors. To investigate the mecha-nisms and pathways enabling resistance to BRAF inhibitors in melanomas, we integrate expression, ATAC-seq, and CRISPR screen data. We identify the JUN family transcription factors and the ETS family transcription factor ETV5 as key regulators of CDK6, which together enable resistance to BRAF inhibitors in melanoma cells. Our findings reveal genes contributing to resistance to a selective BRAF inhibitor PLX4720, providing new insights into gene regulation in BRAF inhibitor resistant melanoma cells.
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