Proteomic analyses identify targets, pathways, and cellular consequences of oncogenic KRAS signaling

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Mutations that activate the small GTPase KRAS are a frequent genetic alteration in cancer, and drug discovery efforts have led to inhibitors that block KRAS activity. We sought to better understand oncogenic KRAS signaling and the cytostatic effects of drugs that target this system. We performed proteomic analyses to investigate changes in protein abundance and posttranslational modifications in inhibitor-treated human KRAS-mutant pancreatic (KRAS G12C and G12D) and lung cancer (KRAS G12C) cells. The inhibitors used target these mutant forms of KRAS, the downstream effectors MEK and ERK, and the upstream regulators SHP2 and SOS1. Comparisons of phosphoproteomes between cell lines revealed a core KRAS signaling signature and cell line–specific signaling networks. In all cell lines, phosphoproteomes were dominated by different degrees of autonomous, oncogenic KRAS activity. Comparison of phosphoproteomes after short and long drug exposures revealed the temporal dynamics of KRAS-MEK-ERK axis inhibition that resulted in cell cycle exit. This transition to a quiescent state occurred in the absence of substantial proteome remodeling but included broad changes in protein phosphorylation and ubiquitylation. The collective data reveal insights into oncogenic KRAS signaling, place many additional proteins into this functional context, and implicate cell cycle exit as a mechanism by which cells evade death upon KRAS signaling inhibition.

 

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Kabella N, Bayer FP, Stamatiou S, Abele M, Sakhteman A, Chang Y-C, Wagner V, Gabriel A, Krumm J*, Reinecke M*, Holzner M*, Aigner M, The M, Hahne H*, Bassermann F, Ludwig C, Vagnarelli P & Kuster B^†. Proteomic analyses identify targets, pathways, and cellular consequences of oncogenic KRAS signaling. Science Signaling 18, 6552 (2025).

*Momentum Employee (or former OmicScouts employee)
^†Momentum Scientific Advisory Board Member