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.

Details

Title
Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis
Author
Santana-Codina, Naiara 1 ; Roeth, Anjali A 2 ; Zhang, Yi 1 ; Annan Yang 1 ; Mashadova, Oksana 3 ; Asara, John M 4 ; Wang, Xiaoxu 1 ; Bronson, Roderick T 5 ; Lyssiotis, Costas A 6   VIAFID ORCID Logo  ; Haoqiang Ying 7 ; Kimmelman, Alec C 8 

1  Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA 
2  Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany 
3  Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA 
4  Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA 
5  Rodent Histopathology Core, Harvard Medical School, Boston, MA, USA 
6  Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA; Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA 
7  Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 
8  Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Radiation Oncology, Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA 
Pages
1-13
Publication year
2018
Publication date
Nov 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-07472-8
ProQuest document ID
2137122596
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.