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, patients frequently develop drug resistance. To identify candidate therapeutic targets for BRAF inhibitor 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 mechanisms 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.
Highlights
Melanoma is an aggressive malignancy with a poor prognosis
There is no BRAF amplification and alternative splicing variants confer BRAF inhibitors (BRAFi) resistance in this cell lines [25]. This indicates that the drug resistance acquired by M238R1 is not due to a new genetic alteration inside the BRAF coding region
Among the network of genes whose β score decreased after drug treatment, we found that the ERBB2 signaling pathway, RAS pathway, ERK pathway, MAPK pathway, and EGFR signaling pathway are highly enriched
Summary
Melanoma is an aggressive malignancy with a poor prognosis. The median survival for patients with stage IV melanoma ranges from 8 to 18 months after diagnosis, depending on the substage [1]. Somatic mutations in BRAF, most commonly V600E or V600K [2], are the most frequently identified cancer-causing mutations in melanoma, and recurrently appear in colorectal cancer, non-small cell lung carcinoma, and many other cancers [3]. BRAF encodes a protein belonging to the RAF family of serine/threonine protein kinases. This protein plays a role in regulating the ERK signaling pathway, which affects cell division, differentiation, and cell death [4]. The RAS–RAF–MEK–ERK pathway mediates intracellular responses to growth signals and plays an essential role in tumor progression and metastasis [5]
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