IDH1 Mutations Alter Citric Acid Cycle Metabolism and Increase Dependence on Oxidative Mitochondrial Metabolism

TLDR

Oncogenic IDH1/2 mutations occur in several cancers, yet their metabolic effects remain incompletely understood. The study aimed to characterize metabolic fluxes in isogenic cell lines with heterozygous IDH1/2 mutations using 13C metabolic flux analysis. 13C metabolic flux analysis was performed on isogenic cell lines harboring heterozygous IDH1/2 mutations. Under hypoxia, IDH1‑mutant cells showed increased oxidative TCA cycle activity and reduced reductive glutamine metabolism, a defect not reversed by selective IDH1 inhibition, leading to heightened sensitivity to hypoxia or ETC inhibition and impaired growth in hypoxic xenografts, highlighting therapeutic vulnerabilities. Published in Cancer Research 74(12):3317–31, ©2014 AACR.

Abstract

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 13C 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. Cancer Res; 74(12); 3317–31. ©2014 AACR.