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 (mIDH) 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. mIDH genes are associated with a variety of cancers, including but not limited to, cholangiocarcinoma, acute myeloid leukaemia, glioma, and chondrosarcoma, and the incidences of mIDH in these cancers varies and is approximately 13%, 33%, 73%, and 56%, respectively. The biological effects of mIDH are distinct in different cancers, but the reason that mIDH promotes tumour development in some tissues and not others is not clear. mIDH has no definitive prognostic impact in these cancers, except glioma, in which it is a disease-defining marker due to its distinct prognostic significance. mIDH1/2 are actionable mutations that represent therapeutic targets, however available targeted therapies to treat mIDH cancers are lacking. This article discusses mIDH genes and their importance in each of these cancers.