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

AR Grassian, SJ Parker, SM Davidson, AS Divakaruni… - Cancer research, 2014 - AACR
AR Grassian, SJ Parker, SM Davidson, AS Divakaruni, CR Green, X Zhang, KL Slocum…
Cancer research, 2014AACR
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 …
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.
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