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Proc Natl Acad Sci U S A. 2015 Aug 11;112(32):E4410-7. doi: 10.1073/pnas.1501605112. Epub 2015 Jul 27.

Metabolite profiling stratifies pancreatic ductal adenocarcinomas into subtypes with distinct sensitivities to metabolic inhibitors.

Author information

1
Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080;
2
Discovery Oncology, Genentech, South San Francisco, CA 94080;
3
Translational Oncology, Genentech, South San Francisco, CA 94080;
4
Biochemical Pharmacology, Genentech, South San Francisco, CA 94080.
5
Discovery Oncology, Genentech, South San Francisco, CA 94080; evangelista.marie@gene.com.

Abstract

Although targeting cancer metabolism is a promising therapeutic strategy, clinical success will depend on an accurate diagnostic identification of tumor subtypes with specific metabolic requirements. Through broad metabolite profiling, we successfully identified three highly distinct metabolic subtypes in pancreatic ductal adenocarcinoma (PDAC). One subtype was defined by reduced proliferative capacity, whereas the other two subtypes (glycolytic and lipogenic) showed distinct metabolite levels associated with glycolysis, lipogenesis, and redox pathways, confirmed at the transcriptional level. The glycolytic and lipogenic subtypes showed striking differences in glucose and glutamine utilization, as well as mitochondrial function, and corresponded to differences in cell sensitivity to inhibitors of glycolysis, glutamine metabolism, lipid synthesis, and redox balance. In PDAC clinical samples, the lipogenic subtype associated with the epithelial (classical) subtype, whereas the glycolytic subtype strongly associated with the mesenchymal (QM-PDA) subtype, suggesting functional relevance in disease progression. Pharmacogenomic screening of an additional ∼ 200 non-PDAC cell lines validated the association between mesenchymal status and metabolic drug response in other tumor indications. Our findings highlight the utility of broad metabolite profiling to predict sensitivity of tumors to a variety of metabolic inhibitors.

KEYWORDS:

biomarkers for metabolic inhibitors; glycolysis; lipid synthesis; metabolic subtypes in PDAC; metabolite profiling

PMID:
26216984
PMCID:
PMC4538616
DOI:
10.1073/pnas.1501605112
[Indexed for MEDLINE]
Free PMC Article

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