KRAS G12C inhibition produces a driver-limited state revealing collateral dependencies

Inhibitors targeting KRAS , a mutant form of the guanosine triphosphatase (GTPase) KRAS, are a promising new class of oncogene-specific therapeutics for the treatment of tumors driven by the mutant protein. These inhibitors react with the mutant cysteine residue by binding covalently to the switch-I...

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Bibliographic Details
Published in:	Science signaling Vol. 12; no. 583
Main Authors:	Lou, Kevin, Steri, Veronica, Ge, Alex Y, Hwang, Y Christina, Yogodzinski, Christopher H, Shkedi, Arielle R, Choi, Alex L M, Mitchell, Dominique C, Swaney, Danielle L, Hann, Byron, Gordan, John D, Shokat, Kevan M, Gilbert, Luke A
Format:	Journal Article
Language:	English
Published:	United States 28-05-2019
Subjects:	Animals Antineoplastic Agents - pharmacology Cell Line, Tumor Cell Proliferation - drug effects CRISPR-Cas Systems Cysteine - genetics Female Genomics HEK293 Cells Humans Lung Neoplasms - genetics Lung Neoplasms - metabolism Mice Mice, Nude Mutation Neoplasm Transplantation Oncogenes Pancreatic Neoplasms - genetics Pancreatic Neoplasms - metabolism Protein Binding Proteomics Proto-Oncogene Proteins p21(ras) - antagonists & inhibitors Proto-Oncogene Proteins p21(ras) - genetics Sequence Analysis, RNA Signal Transduction - drug effects
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Summary:	Inhibitors targeting KRAS , a mutant form of the guanosine triphosphatase (GTPase) KRAS, are a promising new class of oncogene-specific therapeutics for the treatment of tumors driven by the mutant protein. These inhibitors react with the mutant cysteine residue by binding covalently to the switch-II pocket (S-IIP) that is present only in the inactive guanosine diphosphate (GDP)-bound form of KRAS , sparing the wild-type protein. We used a genome-scale CRISPR interference (CRISPRi) functional genomics platform to systematically identify genetic interactions with a KRAS inhibitor in cellular models of KRAS mutant lung and pancreatic cancer. Our data revealed genes that were selectively essential in this oncogenic driver-limited cell state, meaning that their loss enhanced cellular susceptibility to direct KRAS inhibition. We termed such genes "collateral dependencies" (CDs) and identified two classes of combination therapies targeting these CDs that increased KRAS target engagement or blocked residual survival pathways in cells and in vivo. From our findings, we propose a framework for assessing genetic dependencies induced by oncogene inhibition.
ISSN:	1937-9145
DOI:	10.1126/scisignal.aaw9450