Oncogenic KRAS engages an RSK1/NF1 pathway to inhibit wild-type RAS signaling in pancreatic cancer
Derek Cheng, Tobiloba E. Oni, Jennifer S. Thalappillil, Youngkyu Park, Hsiu-Chi Ting, Brinda Alagesan, Nadia V. Prasad, Kenneth J. Addison, Keith Rivera, Darryl Pappin, Linda Van Aelst, David A. Tuveson
Abstract
Significance For decades, KRAS interactors have been sought after as potential therapeutic targets in KRAS mutant cancers, especially pancreatic ductal adenocarcinoma (PDAC). Our proximity labeling screen with KRAS in PDAC cells highlights RSK1 as a notable mutant-specific interactor. Functionally, we show that RSK1 mediates negative feedback on wild-type (WT) KRAS in PDAC cells. Targeting oncogenic KRAS eliminates the negative feedback on WT RAS and highlights a role for WT RAS signaling in promoting adaptive resistance to mutant KRAS ablation.