Open AccessOncogenic KRAS engages an RSK1/NF1 pathway to inhibit wild-type RAS signaling in pancreatic cancer
Author(s) -
Derek Cheng,
Tobiloba E. Oni,
Jennifer S. Thalappillil,
Young-Kyu Park,
Hsiu-Chi Ting,
Brinda Alagesan,
Nadia V Prasad,
Kenneth J. Addison,
Keith Rivera,
Darryl Pappin,
Linda Van Aelst,
David A. Tuveson
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2016904118
Subject(s) - kras , pancreatic cancer , cancer research , biology , hras , mutant , effector , signal transduction , cancer , microbiology and biotechnology , biochemistry , genetics , colorectal cancer , gene
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.