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Cell Rep DOI:10.1016/j.celrep.2019.08.090

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

Publication TypeJournal Article
Year of Publication2019
AuthorsSulahian, 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
JournalCell Rep
Volume29
Issue1
Pages118-134.e8
Date Published2019 Oct 01
ISSN2211-1247
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.

DOI10.1016/j.celrep.2019.08.090
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/31577942?dopt=Abstract

Alternate JournalCell Rep
PubMed ID31577942