Proteomics,Multiomics

Dataset Information

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KRASG12C inhibition produces a driver-limited state revealing collateral dependencies


ABSTRACT: Inhibitors targeting KRASG12C are a promising new class of oncogene-specific therapeutics for the treatment of tumors driven by KRASG12C mutations. These molecules react with the mutant cysteine residue by binding covalently to the switch-II pocket present only in the inactive-GDP state of KRASG12C, sparing the wild type protein. We systematically probe genetic interactions with direct KRASG12C inhibition in cellular models of KRASG12C mutant lung and pancreatic cancer using a genome-scale CRISPR interference (CRISPRi) functional genomics platform. Our data reveal that repression of genes selectively essential in an oncogenic driverlimited cell state, which we term collateral dependencies (CDs), enhances cellular susceptibility to direct KRASG12C inhibition. We nominate two classes of combination therapies targeting CDs that increase KRASG12C target engagement or block residual survival pathways. We demonstrate in vitro and in vivo that both classes enhance response to anti-KRASG12C therapy and propose a new framework for assessing genetic dependencies with driver oncogenes.

OTHER RELATED OMICS DATASETS IN: GSE130616

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Danielle Swaney  

LAB HEAD: John D. Gordan

PROVIDER: PXD013075 | Pride | 2020-03-23

REPOSITORIES: Pride

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Publications


Inhibitors targeting KRAS<sup>G12C</sup>, 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<sup>G12C</sup>, sparing the wild-type protein. We used a genome-scale CRISPR interfer  ...[more]

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