Synthetic Lethal Interaction of SHOC2 Depletion with MEK Inhibition in RAS-Driven Cancers
| Autor: | Rosy Liao, Joshua Pan, Raymond W.S. Ng, Federica Piccioni, Jonathan P. Rennhack, Ari J. Firestone, William C. Hahn, Amy Goodale, Diego Almanza, Andrew J. Aguirre, John A. Bachman, Emma Pailler, David E. Root, Srivatsan Raghavan, Tina L. Yuan, Mukta Bagul, Nathanael S. Gray, Alfredo Gonzalez, Yenarae Lee, Jason J. Kwon, Katherine H. Walsh, Nancy Dumont, Timothy L. Bosse, Behnam Nabet, Francisca Vazquez, Jeff Settleman, Aviad Tsherniak, Joshua M. Dempster, Adrija J. Navarro, Maneesha Thaker, Rita Sulahian |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Combination therapy MAP Kinase Signaling System Regulator Mice SCID General Biochemistry Genetics and Molecular Biology Receptor tyrosine kinase Article 03 medical and health sciences Mice 0302 clinical medicine Cell Line Tumor Neoplasms Animals Humans Protein kinase A Protein Kinase Inhibitors lcsh:QH301-705.5 Cell Proliferation Mice Hairless biology Effector Chemistry Intracellular Signaling Peptides and Proteins HCT116 Cells 030104 developmental biology lcsh:Biology (General) Cell culture A549 Cells Cancer cell Cancer research biology.protein ras Proteins Mitogen-Activated Protein Kinases 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Cell Reports, Vol 29, Iss 1, Pp 118-134.e8 (2019) |
| ISSN: | 2211-1247 |
| Popis: | Summary: 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. : Sulahian, Kwon, and Walsh et al. performed several loss-of-function CRISPR-Cas9 screens in KRAS-mutant cancer cells treated with a MEK inhibitor and define the landscape of modifiers of MEK inhibitor sensitivity while highlighting that SHOC2 is a potent synthetic lethal target that serves as a critical signaling node to mediate MAP kinase pathway reactivation upon MEK inhibition. Keywords: Ras, KRAS, MEK inhibitor, synthetic lethal, SHOC2, CRISPR-Cas9 screen |
| Databáze: | OpenAIRE |
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