Analysis of CRISPR-Cas9 screens identifies genetic dependencies in melanoma

Pigment Cell Melanoma Res. 2021 Jan;34(1):122-131. doi: 10.1111/pcmr.12919. Epub 2020 Sep 7.

Abstract

Targeting the MAPK signaling pathway has transformed the treatment of metastatic melanoma. CRISPR-Cas9 genetic screens provide a genome-wide approach to uncover novel genetic dependencies that might serve as therapeutic targets. Here, we analyzed recently reported CRISPR-Cas9 screens comparing data from 28 melanoma cell lines and 313 cell lines of other tumor types in order to identify fitness genes related to melanoma. We found an average of 1,494 fitness genes in each melanoma cell line. We identified 33 genes, inactivation of which specifically reduced the fitness of melanoma. This set of tumor type-specific genes includes established melanoma fitness genes as well as many genes that have not previously been associated with melanoma growth. Several genes encode proteins that can be targeted using available inhibitors. We verified that genetic inactivation of DUSP4 and PPP2R2A reduces the proliferation of melanoma cells. DUSP4 encodes an inhibitor of ERK, suggesting that further activation of MAPK signaling activity through its loss is selectively deleterious to melanoma cells. Collectively, these data present a resource of genetic dependencies in melanoma that may be explored as potential therapeutic targets.

Keywords: CRISPR-Cas9 screen; DUSP4; MAPK signaling pathway; PPP2R2A; melanoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CRISPR-Cas Systems*
  • Cell Proliferation
  • Dual-Specificity Phosphatases / antagonists & inhibitors*
  • Dual-Specificity Phosphatases / genetics
  • Dual-Specificity Phosphatases / metabolism
  • Gene Knockout Techniques / methods*
  • Genome, Human*
  • Humans
  • Melanoma / genetics
  • Melanoma / metabolism
  • Melanoma / pathology*
  • Mitogen-Activated Protein Kinase Phosphatases / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase Phosphatases / genetics
  • Mitogen-Activated Protein Kinase Phosphatases / metabolism
  • Protein Phosphatase 2 / antagonists & inhibitors*
  • Protein Phosphatase 2 / genetics
  • Protein Phosphatase 2 / metabolism
  • Tumor Cells, Cultured

Substances

  • PPP2R2A protein, human
  • Mitogen-Activated Protein Kinase Phosphatases
  • Protein Phosphatase 2
  • DUSP4 protein, human
  • Dual-Specificity Phosphatases