Journal
CELL REPORTS
Volume 22, Issue 7, Pages 1889-1902Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2018.01.051
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Funding
- NIH from CTD2 network [5U01CA168370]
- Susan G. Komen Foundation [KG111338]
- Daiichi-Sankyo
- Wellcome Trust [102696]
- Stand Up To Cancer [SU2C-AACR-DT17-15]
- National Cancer Institute, NIH [HHSN261200800001E]
- NIH [K99 CA194284-02]
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KRAS can bind numerous effector proteins, which activate different downstream signaling events. The best known are RAF, phosphatidylinositide (PI)-3' kinase, and RalGDS families, but many additional direct and indirect effectors have been reported. We have assessed how these effectors contribute to several major phenotypes in a quantitative way, using an arrayed combinatorial siRNA screen in which we knocked down 41 KRAS effectors nodes in 92 cell lines. We show that every cell line has a unique combination of effector dependencies, but in spite of this heterogeneity, we were able to identify two major subtypes of KRAS mutant cancers of the lung, pancreas, and large intestine, which reflect different KRAS effector engagement and opportunities for therapeutic intervention.
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