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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
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.
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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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