Differential Effector Engagement by Oncogenic KRAS

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. [Display omitted] •Multi-paralog knockdown mitigates redundancy issues in RNAi screening•Oncogenic KRAS can differentially engage effector pathways•There are two major subtypes of KRAS mutant cancer, dependent on KRAS or RSK•KRAS mutant subtypes differ in their morphological and metabolic states Oncogenic KRAS promotes multiple transformation phenotypes, including uncontrolled proliferation, loss of contact inhibition, and altered metabolism. This range of phenotypes may relate to the numerous effector pathways that KRAS activates. Yuan et al. assess how these effectors contribute to these phenotypes using a combinatorial siRNA screen.