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Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis
Oncogenic KRAS is the key driver of pancreatic ductal adenocarcinoma (PDAC). We previously described a role for KRAS in PDAC tumor maintenance through rewiring of cellular metabolism to support proliferation. Understanding the details of this metabolic reprogramming in human PDAC may provide novel t...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251888/ https://www.ncbi.nlm.nih.gov/pubmed/30470748 http://dx.doi.org/10.1038/s41467-018-07472-8 |
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author | Santana-Codina, Naiara Roeth, Anjali A. Zhang, Yi Yang, Annan Mashadova, Oksana Asara, John M. Wang, Xiaoxu Bronson, Roderick T. Lyssiotis, Costas A. Ying, Haoqiang Kimmelman, Alec C. |
author_facet | Santana-Codina, Naiara Roeth, Anjali A. Zhang, Yi Yang, Annan Mashadova, Oksana Asara, John M. Wang, Xiaoxu Bronson, Roderick T. Lyssiotis, Costas A. Ying, Haoqiang Kimmelman, Alec C. |
author_sort | Santana-Codina, Naiara |
collection | PubMed |
description | Oncogenic KRAS is the key driver of pancreatic ductal adenocarcinoma (PDAC). We previously described a role for KRAS in PDAC tumor maintenance through rewiring of cellular metabolism to support proliferation. Understanding the details of this metabolic reprogramming in human PDAC may provide novel therapeutic opportunities. Here we show that the dependence on oncogenic KRAS correlates with specific metabolic profiles that involve maintenance of nucleotide pools as key mediators of KRAS-dependence. KRAS promotes these effects by activating a MAPK-dependent signaling pathway leading to MYC upregulation and transcription of the non-oxidative pentose phosphate pathway (PPP) gene RPIA, which results in nucleotide biosynthesis. The use of MEK inhibitors recapitulates the KRAS-dependence pattern and the expected metabolic changes. Antagonizing the PPP or pyrimidine biosynthesis inhibits the growth of KRAS-resistant cells. Together, these data reveal differential metabolic rewiring between KRAS-resistant and sensitive cells, and demonstrate that targeting nucleotide metabolism can overcome resistance to KRAS/MEK inhibition. |
format | Online Article Text |
id | pubmed-6251888 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-62518882018-11-26 Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis Santana-Codina, Naiara Roeth, Anjali A. Zhang, Yi Yang, Annan Mashadova, Oksana Asara, John M. Wang, Xiaoxu Bronson, Roderick T. Lyssiotis, Costas A. Ying, Haoqiang Kimmelman, Alec C. Nat Commun Article Oncogenic KRAS is the key driver of pancreatic ductal adenocarcinoma (PDAC). We previously described a role for KRAS in PDAC tumor maintenance through rewiring of cellular metabolism to support proliferation. Understanding the details of this metabolic reprogramming in human PDAC may provide novel therapeutic opportunities. Here we show that the dependence on oncogenic KRAS correlates with specific metabolic profiles that involve maintenance of nucleotide pools as key mediators of KRAS-dependence. KRAS promotes these effects by activating a MAPK-dependent signaling pathway leading to MYC upregulation and transcription of the non-oxidative pentose phosphate pathway (PPP) gene RPIA, which results in nucleotide biosynthesis. The use of MEK inhibitors recapitulates the KRAS-dependence pattern and the expected metabolic changes. Antagonizing the PPP or pyrimidine biosynthesis inhibits the growth of KRAS-resistant cells. Together, these data reveal differential metabolic rewiring between KRAS-resistant and sensitive cells, and demonstrate that targeting nucleotide metabolism can overcome resistance to KRAS/MEK inhibition. Nature Publishing Group UK 2018-11-23 /pmc/articles/PMC6251888/ /pubmed/30470748 http://dx.doi.org/10.1038/s41467-018-07472-8 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Santana-Codina, Naiara Roeth, Anjali A. Zhang, Yi Yang, Annan Mashadova, Oksana Asara, John M. Wang, Xiaoxu Bronson, Roderick T. Lyssiotis, Costas A. Ying, Haoqiang Kimmelman, Alec C. Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis |
title | Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis |
title_full | Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis |
title_fullStr | Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis |
title_full_unstemmed | Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis |
title_short | Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis |
title_sort | oncogenic kras supports pancreatic cancer through regulation of nucleotide synthesis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251888/ https://www.ncbi.nlm.nih.gov/pubmed/30470748 http://dx.doi.org/10.1038/s41467-018-07472-8 |
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