Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis

Naiara Santana-Codina, Anjali A. Roeth, Yi Zhang, Annan Yang, Oksana Mashadova, John M. Asara, Xiaoxu Wang, Roderick T. Bronson, Costas A. Lyssiotis, Haoqiang Ying and Alec C. Kimmelman ()
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Naiara Santana-Codina: Dana-Farber Cancer Institute
Anjali A. Roeth: Dana-Farber Cancer Institute
Yi Zhang: Dana-Farber Cancer Institute
Annan Yang: Dana-Farber Cancer Institute
Oksana Mashadova: Weill Cornell Medicine
John M. Asara: Beth Israel Deaconess Medical Center and Harvard Medical School
Xiaoxu Wang: Dana-Farber Cancer Institute
Roderick T. Bronson: Harvard Medical School
Costas A. Lyssiotis: University of Michigan
Haoqiang Ying: The University of Texas MD Anderson Cancer Center
Alec C. Kimmelman: Dana-Farber Cancer Institute

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-07472-8

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