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 13C-metabolic flux analysis (MFA) 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 (TCA) 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 (ETC) inhibition in vitro. Lastly, IDH1 mutant cells also grew poorly as subcutaneous xenografts within an hypoxic in vivo microenvironment. Together, our results suggest therapeutic opportunities to exploit the metabolic vulnerabilities specific to IDH1 mutation.
- Received March 14, 2014.
- Accepted March 21, 2014.
- Copyright © 2013, American Association for Cancer Research.