Differential Effector Engagement by Oncogenic KRAS.

Graphical Abstract of Differential Effector Engagement by Oncogenic KRAS Article.

Copyright © 2017 Elsevier B.V.

Yuan TL, Amzallag A, Bagni R, Yi M, Afghani S, Burgan W, Fer N, Strathern LA, Powell K, Smith B, Waters AM, Drubin D, Thomson T, Liao R, Greninger P, Stein GT, Murchie E, Cortez E, Egan RK, Procter L, Bess M, Cheng KT, Lee CS, Lee LC, Fellmann C, Stephens R, Luo J, Lowe SW, Benes CH, McCormick F

Cell Reports

February 13, 2018

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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Last updated: March 05, 2018