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

• DOI: 10.1126/scisignal.aaw9450
• Publication Date: 2019-05-28T23:55:17Z
• Authors: Kevin Lou; Veronica Steri; Alex Y. Ge; Y. Christina Hwang; Christopher H. Yo...; Arielle R. Shkedi; Alex L. M. Choi; Dominique C. Mitc...; Danielle L. Swaney; Byron Hann; John D. Gordan; Kevan M. Shokat; Luke A. Gilbert
• Keywords: Small GTPase; HRAS

Inhibitors targeting KRASG12C, a mutant form of the guanosine triphosphatase (GTPase) KRAS, are promising new class oncogene-specific therapeutics for treatment tumors driven by protein. These inhibitors react with cysteine residue binding covalently to switch-II pocket (S-IIP) that is present only in inactive diphosphate (GDP)-bound sparing wild-type We used genome-scale CRISPR interference (CRISPRi) functional genomics platform systematically identify genetic interactions KRASG12C inhibitor cellular models lung and pancreatic cancer. Our data revealed genes were selectively essential this oncogenic driver-limited cell state, meaning their loss enhanced susceptibility direct inhibition. termed such "collateral dependencies" (CDs) identified two classes combination therapies these CDs increased target engagement or blocked residual survival pathways cells vivo. From our findings, we propose framework assessing dependencies induced oncogene