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Oncogenic KRAS engages an RSK1/NF1 pathway to inhibit wild-type RAS signaling in pancreatic cancer
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 targ...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166058/ https://www.ncbi.nlm.nih.gov/pubmed/34021083 http://dx.doi.org/10.1073/pnas.2016904118 |
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author | 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. |
author_facet | 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. |
author_sort | Cheng, Derek K. |
collection | PubMed |
description | 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-KRAS4B(G12D)), and nontransforming cytosolic double mutant (BirA-KRAS4B(G12D/C185S)) KRAS with the BirA biotin ligase in murine PDAC cells. Mass spectrometry analysis revealed that RSK1 selectively interacts with membrane-bound KRAS(G12D), 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. |
format | Online Article Text |
id | pubmed-8166058 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-81660582021-06-10 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. Proc Natl Acad Sci U S A Biological Sciences 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-KRAS4B(G12D)), and nontransforming cytosolic double mutant (BirA-KRAS4B(G12D/C185S)) KRAS with the BirA biotin ligase in murine PDAC cells. Mass spectrometry analysis revealed that RSK1 selectively interacts with membrane-bound KRAS(G12D), 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. National Academy of Sciences 2021-05-25 2021-05-21 /pmc/articles/PMC8166058/ /pubmed/34021083 http://dx.doi.org/10.1073/pnas.2016904118 Text en Copyright © 2021 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences 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. Oncogenic KRAS engages an RSK1/NF1 pathway to inhibit wild-type RAS signaling in pancreatic cancer |
title | Oncogenic KRAS engages an RSK1/NF1 pathway to inhibit wild-type RAS signaling in pancreatic cancer |
title_full | Oncogenic KRAS engages an RSK1/NF1 pathway to inhibit wild-type RAS signaling in pancreatic cancer |
title_fullStr | Oncogenic KRAS engages an RSK1/NF1 pathway to inhibit wild-type RAS signaling in pancreatic cancer |
title_full_unstemmed | Oncogenic KRAS engages an RSK1/NF1 pathway to inhibit wild-type RAS signaling in pancreatic cancer |
title_short | Oncogenic KRAS engages an RSK1/NF1 pathway to inhibit wild-type RAS signaling in pancreatic cancer |
title_sort | oncogenic kras engages an rsk1/nf1 pathway to inhibit wild-type ras signaling in pancreatic cancer |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166058/ https://www.ncbi.nlm.nih.gov/pubmed/34021083 http://dx.doi.org/10.1073/pnas.2016904118 |
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