Research ArticleCancer therapy

KRASG12C inhibition produces a driver-limited state revealing collateral dependencies

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Science Signaling  28 May 2019:
Vol. 12, Issue 583, eaaw9450
DOI: 10.1126/scisignal.aaw9450

Getting ahead of KRAS inhibitor resistance

The growth of many cancers is driven by mutations in the gene KRAS. Although the encoded protein has been considered “undruggable,” the compound ARS-1620 binds to and inhibits one of these KRAS mutants (termed G12C) and is showing promising results in clinical trials. Lou et al. sought combination therapies that could enhance the efficacy of ARS-1620 and possibly prevent therapeutic resistance. Using functional genomics that identified pathway rewiring in ARS-1620–treated lung and pancreatic cancer cells, the authors found combination therapies that either enhanced target engagement by ARS-1620 (namely, EGFR, FGFR, or SHP2 inhibitors) or suppressed persistent tumor cell survival pathways (namely, AXL, PI3K, or CDK4/6 inhibitors). The findings have promising implications for clinical success for patients.


Inhibitors targeting KRASG12C, 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 KRASG12C, sparing the wild-type protein. We used a genome-scale CRISPR interference (CRISPRi) functional genomics platform to systematically identify genetic interactions with a KRASG12C inhibitor in cellular models of KRASG12C 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 KRASG12C inhibition. We termed such genes “collateral dependencies” (CDs) and identified two classes of combination therapies targeting these CDs that increased KRASG12C 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.

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