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

Rita Sulahian1, Jason J Kwon2, Katherine H Walsh1

  • 1Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Cell Reports
|October 3, 2019
PubMed

Insights

Combining MEK inhibitors with SHOC2 targeting shows promise for RAS-driven cancers. Depleting SHOC2 disrupts survival pathways, impairing proliferation in KRAS-mutant pancreatic and lung cancer cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The mitogen-activated protein kinase (MAPK) pathway is crucial in oncogenic RAS signaling.
  • Targeting the MAPK pathway, particularly with MEK inhibitors (MEKi), is a potential combination treatment strategy for cancers.

Purpose of the Study:

  • To identify genes that cooperate with MEK inhibition in KRAS-mutant pancreatic and lung cancer.
  • To explore synthetic lethal interactions and novel therapeutic targets for RAS-driven cancers.

Main Methods:

  • Genome-scale loss-of-function CRISPR-Cas9 screens were conducted in KRAS-mutant cancer cell lines treated with a MEK1/2 inhibitor.
  • Investigated the role of specific genes, including SHOC2, in sensitizing cancer cells to MEK inhibition.

Main Results:

  • Identified recurrent classes of synthetic lethal vulnerabilities at the pathway level, with several receptor tyrosine kinase (RTK)-RAS-MAPK pathway members sensitizing cells to MEKi.
  • Demonstrated that SHOC2 (a positive regulator of MAPK signaling) knockout, suppression, or degradation specifically cooperated with MEK inhibition to impair cancer cell proliferation.
  • Showed that SHOC2 depletion disrupted survival pathways activated by feedback RTK signaling in response to MEK inhibition.

Conclusions:

  • SHOC2 is a key sensitizer to MEK inhibition in RAS-driven cancers.
  • Targeting SHOC2 in combination with MEK inhibitors presents a potential therapeutic strategy for treating KRAS-mutant pancreatic and lung cancers.
Keywords:
CRISPR-Cas9 screenKRASMEK inhibitorRasSHOC2synthetic lethal

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