Journal
CELL REPORTS
Volume 29, Issue 1, Pages 118-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2019.08.090
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Funding
- Calico Life Sciences
- NIH-National Cancer Institute (NCI) [F32CA243290]
- Fondation pour la Recherche Medicale [SPE2018035027]
- Lustgarten Foundation
- Dana-Farber Cancer Institute Hale Center for Pancreatic Cancer Research
- Hope Funds for Cancer Research
- Doris Duke Charitable Foundation
- Pancreatic Cancer Action Network
- American Cancer Society Postdoctoral Fellowship [PF-17-010-01-CDD]
- Conquer Cancer Foundation of ASCO Young Investigator Award
- NIH-NCI [K08 CA218420-02, P50CA127003, U01 CA224146, U01 CA199253, K00CA212221]
- Harvard Clinical and Translational Science Center [UL1 TR001102]
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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.
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