Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis
Open accessAbstract
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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KRAS mutations lead to sustained activation of MAPK and PI3K-mTOR pathways.
“KRAS mutations lead to sustained activation of MAPK and PI3K-mTOR pathways16,17”
From Dynamic IL-6R/STAT3 signaling leads to heterogeneity of metabolic phenotype in pancreatic ductal adenocarcinoma cells (2024) · cites this paper as [17]
The Results section, “The MAPK-MYC-RPIA pathway mediates KRAS resistance” (page unavailable), supports KRAS-dependent MAPK signaling: KRAS depletion decreased ERK phosphorylation. It does not establish sustained PI3K-mTOR activation by KRAS mutations; it reports only a minor effect of KRAS depletion on AKT and describes PI3K activation as a compensatory response to MEK inhibition. (LLM, conf=0.86)
Experimental — accuracy not yet measuredPancreatic cancers generate substantial lactic acid fluxes, linked to mutations that promote hyper-proliferation.
“pancreatic cancers generate substantial lactic acid fluxes, linked to mutations that promote hyper-proliferation”
From Dynamic IL-6R/STAT3 signaling leads to heterogeneity of metabolic phenotype in pancreatic ductal adenocarcinoma cells (2024) · cites this paper as [17]
The Results section ('Kras dependency correlates with differential metabolic rewiring'; page unavailable) reports that KRAS depletion reduced glycolytic intermediates and extracellular acidification in human pancreatic cancer cell lines, supporting a link between an oncogenic mutation and altered metabolism. The Methods ('Metabolism studies'; page unavailable) describe measuring lactate production, but the retrieved passages do not establish that pancreatic cancers generate substantial lactic acid fluxes or directly link such fluxes to hyper-proliferation. (LLM, conf=0.82)
Experimental — accuracy not yet measuredKRAS regulates these metabolic pathways through MAPK-dependent signaling, supporting survival and conferring a proliferative advantage on tumors.
“KRAS regulates these pathways through MAPK-dependent signaling cascades, ultimately supporting cell survival and conferring a proliferative advantage on tumors28,36,37.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [37]
In pancreatic cancer cells, oncogenic K-Ras maintains the nucleotide pool via the MAPK-dependent signaling pathway, leading to MYC upregulation, and MEK inhibitors reduce incorporation of glutamine-derived nitrogen into purine nucleotides.
“In pancreatic cancer cells, oncogenic K-Ras maintains the nucleotide pool via the MAPK-dependent signaling pathway, leading to MYC upregulation, and the use of MEK inhibitors reduces the incorporation of glutamine-derived nitrogen into purine nucleotides38.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [38]
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References 49 · Cited by 252
- Authors
- Santana-Codina, N., Roeth, A. A., Zhang, Y., Yang, A., Mashadova, O., Asara, J. M., Wang, X., Bronson, R. T., Lyssiotis, C. A., Ying, H., & Kimmelman, A. C.
- Affiliations
- Dana-Farber Cancer Institute (US)
- Weill Cornell Medicine (US)
- Beth Israel Deaconess Medical Center (US)
- Harvard University (US)
- University of Michigan (US)
- The University of Texas MD Anderson Cancer Center (US)
- NYU Langone Health (US)
- Corresponding author
- Kimmelman, Alec C.
- ORCID
- Venue
- Nature Communications
- Published
- 2018-11-23
- Volume
- 9
- Issue
- 1
- Pages
- 4945-4945
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6251888
- OpenAlex
- W2900616886
- Cited by
- 252
- References
- 49
- Citations by year
- 2026: 27 · 2025: 26 · 2024: 26 · 2023: 39 · 2022: 31 · 2021: 39 · 2020: 45 · 2019: 19
- FWCI
- 9.68
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- RWTH Publications (RWTH Aachen) (submittedVersion, other-oa)
- RWTH Publications (RWTH Aachen)
- Funders
- Lustgarten Foundation
- Dana-Farber/Harvard Cancer Center (P30 CA 06516, 5 P30 CA06516, CA06516, NIH 5 P30 CA06516)
- National Institutes of Health (5 P30 CA06516, CA06516, NIH 5 P30 CA06516)
- National Cancer Institute (NIH5P30CA06516, CA06516, P30-CA06516, R01CA188048, R35CA232124, R01CA157490, P01CA117969, P30CA006516, 5-P30 CA06516)
- National Institute of General Medical Sciences (R01GM095567)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Keywords
- oncogenic KRAS, pancreatic ductal adenocarcinoma, nucleotide synthesis, metabolic reprogramming, pentose phosphate pathway, c-Myc, MAPK signaling, MEK inhibitors, pyrimidine synthesis, cancer metabolism
- MeSH terms
- Animals, Female, Humans, Mice, Nude, Pancreatic Neoplasms, Pentose Phosphate Pathway, Pyrimidines, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins p21(ras), MAP Kinase Signaling System, Carcinoma, Pancreatic Ductal, Protein Kinase Inhibitors, Mice
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