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

Rita Sulahian, Jason J. Kwon, Katherine H. Walsh, Emma Pailler, Timothy L. Bosse, Maneesha Thaker, Diego Almanza, Joshua M. Dempster, Joshua Pan, Federica Piccioni, Nancy Dumont, Alfredo Gonzalez (+19 others)
2019 Cell Reports  
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,
more » ... 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.
doi:10.1016/j.celrep.2019.08.090 pmid:31577942 pmcid:PMC6918830 fatcat:ttlatrftrraybo7dbs72uiljbq