RRC ID 58087
Author Sulahian R, Kwon JJ, Walsh KH, Pailler E, Bosse TL, Thaker M, Almanza D, Dempster JM, Pan J, Piccioni F, Dumont N, Gonzalez A, Rennhack J, Nabet B, Bachman JA, Goodale A, Lee Y, Bagul M, Liao R, Navarro A, Yuan TL, Ng RWS, Raghavan S, Gray NS, Tsherniak A, Vazquez F, Root DE, Firestone AJ, Settleman J, Hahn WC, Aguirre AJ.
Title Synthetic Lethal Interaction of SHOC2 Depletion with MEK Inhibition in RAS-Driven Cancers.
Journal Cell Rep
Abstract 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.
Volume 29(1)
Pages 118-134.e8
Published 2019-10-1
DOI 10.1016/j.celrep.2019.08.090
PII S2211-1247(19)31152-0
PMID 31577942
PMC PMC6918830
MeSH 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*
IF 8.109
Times Cited 3
Human and Animal Cells KP4(RCB1005)