Synthetic Lethal Interaction of SHOC2 Depletion with MEK Inhibition in RAS-Driven Cancers

Cell Rep. 2019 Oct 1;29(1):118-134.e8. doi: 10.1016/j.celrep.2019.08.090.


The mitogen-activated protein kinase (MAPK) pathway is a critical effector of oncogenic RAS signaling, and MAPK pathway inhibition may be an effective combination treatment strategy. We performed genome-scale loss-of-function CRISPR-Cas9 screens in the presence of a MEK1/2 inhibitor (MEKi) in KRAS-mutant pancreatic and lung cancer cell lines and identified genes that cooperate with MEK inhibition. While we observed heterogeneity in genetic modifiers of MEKi sensitivity across cell lines, several recurrent classes of synthetic lethal vulnerabilities emerged at the pathway level. Multiple members of receptor tyrosine kinase (RTK)-RAS-MAPK pathways scored as sensitizers to MEKi. In particular, we demonstrate that knockout, suppression, or degradation of SHOC2, a positive regulator of MAPK signaling, specifically cooperated with MEK inhibition to impair proliferation in RAS-driven cancer cells. The depletion of SHOC2 disrupted survival pathways triggered by feedback RTK signaling in response to MEK inhibition. Thus, these findings nominate SHOC2 as a potential target for combination therapy.

Keywords: CRISPR-Cas9 screen; KRAS; MEK inhibitor; Ras; SHOC2; synthetic lethal.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • A549 Cells
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / physiology
  • HCT116 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology*
  • Mice
  • Mice, Hairless
  • Mice, SCID
  • Mitogen-Activated Protein Kinases / metabolism*
  • Neoplasms / drug therapy
  • Neoplasms / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • ras Proteins / metabolism*


  • Intracellular Signaling Peptides and Proteins
  • Protein Kinase Inhibitors
  • SHOC2 protein, human
  • Mitogen-Activated Protein Kinases
  • ras Proteins