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.

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