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Nat Commun. 2018 Nov 23;9(1):4945. doi: 10.1038/s41467-018-07472-8.

Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis.

Author information

1
Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
2
Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, 52074, Germany.
3
Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA.
4
Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02115, USA.
5
Rodent Histopathology Core, Harvard Medical School, Boston, 02115, MA, USA.
6
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109, USA.
7
Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
8
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, 77030, USA.
9
Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. Alec.Kimmelman@NYUMC.org.
10
Department of Radiation Oncology, Perlmutter Cancer Center, New York University School of Medicine, New York, NY, 10016, USA. Alec.Kimmelman@NYUMC.org.

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.

PMID:
30470748
PMCID:
PMC6251888
DOI:
10.1038/s41467-018-07472-8
[Indexed for MEDLINE]
Free PMC Article

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