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Cancer Res. 2014 Jun 15;74(12):3317-31. doi: 10.1158/0008-5472.CAN-14-0772-T. Epub 2014 Apr 22.

IDH1 mutations alter citric acid cycle metabolism and increase dependence on oxidative mitochondrial metabolism.

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  • 1Authors' Affiliations: Novartis Institutes for Biomedical Research; Koch Institute for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; Departments of Bioengineering and Pharmacology; and Moores Cancer Center, University of California, San Diego, La Jolla, California.
  • 2Authors' Affiliations: Novartis Institutes for Biomedical Research; Koch Institute for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; Departments of Bioengineering and Pharmacology; and Moores Cancer Center, University of California, San Diego, La Jolla, CaliforniaAuthors' Affiliations: Novartis Institutes for Biomedical Research; Koch Institute for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; Departments of Bioengineering and Pharmacology; and Moores Cancer Center, University of California, San Diego, La Jolla, California.
  • 3Authors' Affiliations: Novartis Institutes for Biomedical Research; Koch Institute for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; Departments of Bioengineering and Pharmacology; and Moores Cancer Center, University of California, San Diego, La Jolla, California cmetallo@ucsd.edu raymond.pagliarini@novartis.com.
  • 4Authors' Affiliations: Novartis Institutes for Biomedical Research; Koch Institute for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; Departments of Bioengineering and Pharmacology; and Moores Cancer Center, University of California, San Diego, La Jolla, CaliforniaAuthors' Affiliations: Novartis Institutes for Biomedical Research; Koch Institute for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; Departments of Bioengineering and Pharmacology; and Moores Cancer Center, University of California, San Diego, La Jolla, California cmetallo@ucsd.edu raymond.pagliarini@novartis.com.

Abstract

Oncogenic mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) occur in several types of cancer, but the metabolic consequences of these genetic changes are not fully understood. In this study, we performed (13)C metabolic flux analysis on a panel of isogenic cell lines containing heterozygous IDH1/2 mutations. We observed that under hypoxic conditions, IDH1-mutant cells exhibited increased oxidative tricarboxylic acid metabolism along with decreased reductive glutamine metabolism, but not IDH2-mutant cells. However, selective inhibition of mutant IDH1 enzyme function could not reverse the defect in reductive carboxylation activity. Furthermore, this metabolic reprogramming increased the sensitivity of IDH1-mutant cells to hypoxia or electron transport chain inhibition in vitro. Lastly, IDH1-mutant cells also grew poorly as subcutaneous xenografts within a hypoxic in vivo microenvironment. Together, our results suggest therapeutic opportunities to exploit the metabolic vulnerabilities specific to IDH1 mutation.

©2014 American Association for Cancer Research.

PMID:
24755473
[PubMed - indexed for MEDLINE]
PMCID:
PMC4885639
Free PMC Article
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