Oncogenic KRAS engages an RSK1/NF1 pathway to inhibit wild-type RAS signaling in pancreatic cancer.

Cheng, Derek K, Oni, Tobiloba E, Thalappillil, Jennifer S, Park, Youngkyu, Ting, Hsiu-Chi, Alagesan, Brinda, Prasad, Nadia V, Addison, Kenneth, Rivera, Keith D, Pappin, Darryl J, Van Aelst, Linda, Tuveson, David A (May 2021) Oncogenic KRAS engages an RSK1/NF1 pathway to inhibit wild-type RAS signaling in pancreatic cancer. Proceedings of the National Academy of Sciences of USA, 118 (21). e2016904118-e2016904118. ISSN 0027-8424

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URL: https://www.ncbi.nlm.nih.gov/pubmed/34021083
DOI: 10.1073/pnas.2016904118

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with limited treatment options. Although activating mutations of the KRAS GTPase are the predominant dependency present in >90% of PDAC patients, targeting KRAS mutants directly has been challenging in PDAC. Similarly, strategies targeting known KRAS downstream effectors have had limited clinical success due to feedback mechanisms, alternate pathways, and dose-limiting toxicities in normal tissues. Therefore, identifying additional functionally relevant KRAS interactions in PDAC may allow for a better understanding of feedback mechanisms and unveil potential therapeutic targets. Here, we used proximity labeling to identify protein interactors of active KRAS in PDAC cells. We expressed fusions of wild-type (WT) (BirA-KRAS4B), mutant (BirA-KRAS4BG12D), and nontransforming cytosolic double mutant (BirA-KRAS4BG12D/C185S) KRAS with the BirA biotin ligase in murine PDAC cells. Mass spectrometry analysis revealed that RSK1 selectively interacts with membrane-bound KRASG12D, and we demonstrate that this interaction requires NF1 and SPRED2. We find that membrane RSK1 mediates negative feedback on WT RAS signaling and impedes the proliferation of pancreatic cancer cells upon the ablation of mutant KRAS. Our findings link NF1 to the membrane-localized functions of RSK1 and highlight a role for WT RAS signaling in promoting adaptive resistance to mutant KRAS-specific inhibitors in PDAC.

Item Type: Paper
Subjects: diseases & disorders > cancer > cancer types > pancreatic cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > G protein > Ras
CSHL Authors:
Communities: CSHL labs > Pappin lab
CSHL labs > Tuveson lab
CSHL labs > Van Aelst lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 25 May 2021
Date Deposited: 26 May 2021 14:24
Last Modified: 21 Jun 2021 13:45
PMCID: PMC8166058
Related URLs:
URI: https://repository.cshl.edu/id/eprint/40166

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