Isocitrate dehydrogenase mutations as potential tumour agnostic targets

The isocitrate dehydrogenase (IDH) family of proteins comprises three important metabolic enzymes that convert isocitrate to alpha ketoglutarate (α-KG) via oxidative decarboxylation. The IDH enzymes play important roles in epigenetic regulation, DNA repair, and cellular metabolism and biosynthesis. In mutant IDH (m IDH ) cells, α-KG is converted into the functional oncometabolite 2-hydroxyglutarate (2-HG) in a process that consumes the reduced form of nicotinamide adenine dinucleotide phosphate to generate its oxidised form. 2-HG competitively inhibits α-KG from binding to the active site of histone and DNA demethylases, leading to hypermethylation, which inhibits cellular differentiation and induces tumour cell proliferation. Increased 2-HG also has other effects on cellular biology, including altered metabolism, dysregulation of gene expression, alterations in the DNA damage repair pathway, inflammation, and cell death, therefore supporting and promoting tumorigenesis. m IDH genes are associated with a variety of cancers, including but not limited to, cholangiocarcinoma, acute myeloid leukaemia, glioma, and chondrosarcoma, and the incidences of m IDH in these cancers varies and is approximately 13%, 33%, 73%, and 56%, respectively. The biological effects of m IDH are distinct in different cancers, but the reason that m IDH promotes tumour development in some tissues and not others is not clear. m IDH has no definitive prognostic impact in these cancers, except glioma, in which it is a disease-defining marker due to its distinct prognostic significance. m IDH1 /2 are actionable mutations that represent therapeutic targets, however available targeted therapies to treat m IDH cancers are lacking. This article discusses m IDH genes and their importance in each of these cancers. • Isocitrate dehydrogenase mutations are targetable alterations in several cancers. • Frequency and impact of isocitrate dehydrogenase mutations vary between cancers. • Early molecular testing allows the appropriate treatment option to be determined.