Global proteomics reveals the context-dependence of K-Ras signaling.

KRAS is the most frequently mutated oncogene in cancer. In the absence of direct inhibitors for most K-Ras mutants, therapeutic strategies focus on targeting downstream pathways that mediate its oncogenic properties. This approach is limited, however, by an incomplete understanding of the contextual cues that modulate the signaling output of activated K-Ras. To determine how tissue context, genetic background, and KRAS allele modulate oncogenic signaling on a global level, we performed multiplexed mass spectrometry on mouse tissues expressing wild-type or mutant K-Ras. Different mutant forms of K-Ras dramatically altered the proteomes and phosphoproteomes of colons, pancreases, and spleens, even when a given mutant allele did not alter tissue homeostasis. The vast majority of changes were context specific (i.e., not conserved between tissues or KRAS alleles), leading to several unique K-Ras-regulated network architectures. We developed an approach to integrate proteomic data from mouse models with proteomic and mutational data from human cancers, identifying key nodes in the K-Ras network that are conserved between primary tumors and a model organism. Comparison of the integrated K-Ras signaling networks to genetic screening data identified several genes that are synthetic lethal with mutant K-Ras. Altogether, these studies demonstrate the extreme context-dependent plasticity of K-Ras signaling and identify noncanonical mediators of K-Ras oncogenicity that lie within the K-Ras-regulated signaling network. Citation Format: Kevin Haigis. Global proteomics reveals the context-dependence of K-Ras signaling [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr IA29.