CRISPR Screens Identify Essential Cell Growth Mediators in BRAF Inhibitor-resistant Melanoma

Genomics Proteomics Bioinformatics. 2020 Feb;18(1):26-40. doi: 10.1016/j.gpb.2020.02.002. Epub 2020 May 13.


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.

Keywords: BRAF inhibitor; CRISPR screen; Drug resistance; Gene regulation; Melanoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Clustered Regularly Interspaced Short Palindromic Repeats
  • Drug Resistance, Neoplasm* / genetics
  • Humans
  • Indoles / pharmacology*
  • Intercellular Signaling Peptides and Proteins / physiology*
  • Melanoma / drug therapy*
  • Melanoma / genetics
  • Melanoma / pathology
  • Mutation
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • Proto-Oncogene Proteins B-raf / metabolism
  • Sulfonamides / pharmacology*


  • Indoles
  • Intercellular Signaling Peptides and Proteins
  • PLX 4720
  • Protein Kinase Inhibitors
  • Sulfonamides
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf