Oncogenic KRAS engages an RSK1/NF1 pathway to inhibit wild-type RAS signaling in pancreatic cancer
| Autor: | Young-Kyu Park, Kenneth Addison, Keith Rivera, Jennifer S Thalappillil, Tobiloba E. Oni, Linda Van Aelst, Nadia V Prasad, Derek K. Cheng, Hsiu-Chi Ting, Darryl J. Pappin, David A. Tuveson, Brinda Alagesan |
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| Rok vydání: | 2021 |
| Předmět: |
Medical Sciences
endocrine system diseases Mutant GTPase Biology medicine.disease_cause Ribosomal Protein S6 Kinases 90-kDa Proto-Oncogene Proteins p21(ras) Mice Cell Line Tumor Pancreatic cancer KRAS medicine Animals Humans BioID Pancreas neoplasms Cell Proliferation chemistry.chemical_classification DNA ligase Neurofibromin 1 Multidisciplinary Effector RSK Wild type PDAC Biological Sciences medicine.disease digestive system diseases respiratory tract diseases Repressor Proteins Cytosol chemistry NF1 Mutation Cancer research Carcinoma Pancreatic Ductal Signal Transduction |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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. 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. |
| Databáze: | OpenAIRE |
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