Metabolic adaptations in cancers expressing isocitrate dehydrogenase mutations

The most frequently mutated metabolic genes in human cancer are those encoding the enzymes isocitrate dehydrogenase 1 (IDH1) and IDH2; these mutations have so far been identified in more than 20 tumor types. Since IDH mutations were first reported in glioma over a decade ago, extensive research has revealed their association with altered cellular processes. Mutations in IDH lead to a change in enzyme function, enabling efficient conversion of 2-oxoglutarate to R-2-hydroxyglutarate (R-2-HG). It is proposed that elevated cellular R-2-HG inhibits enzymes that regulate transcription and metabolism, subsequently affecting nuclear, cytoplasmic, and mitochondrial biochemistry. The significance of these biochemical changes for tumorigenesis and potential for therapeutic exploitation remains unclear. Here we comprehensively review reported direct and indirect metabolic changes linked to IDH mutations and discuss their clinical significance. We also review the metabolic effects of first-generation mutant IDH inhibitors and highlight the potential for combination treatment strategies and new metabolic targets.