The implications of IDH mutations for cancer development and therapy

Hotspot genetic alterations that confer the enzymes isocitrate dehydrogenase (IDH) 1 and 2 with neomorphic activity to produce the oncometabolite D-2-hydroxyglutarate are common in several cancer types, including acute myeloid leukaemia, cholangiocarcinoma, chondrosarcoma and glioma. Herein, Pirozzi and Yan describe the current understanding of the biological, pathogenetic and prognostic implications of IDH mutations in these cancers. They also review the available preclinical and clinical data on the various therapeutic strategies that are being pursued for IDH-mutant cancers and discuss whether treatment approaches will converge or be context dependent. Mutations in the genes encoding the cytoplasmic and mitochondrial forms of isocitrate dehydrogenase (IDH1 and IDH2, respectively; collectively referred to as IDH) are frequently detected in cancers of various origins, including but not limited to acute myeloid leukaemia (20%), cholangiocarcinoma (20%), chondrosarcoma (80%) and glioma (80%). In all cases, neomorphic activity of the mutated enzyme leads to production of the oncometabolite D-2-hydroxyglutarate, which has profound cell-autonomous and non-cell-autonomous effects. The broad effects of IDH mutations on epigenetic, differentiation and metabolic programmes, together with their high prevalence across a variety of cancer types, early presence in tumorigenesis and uniform expression in tumour cells, make mutant IDH an ideal therapeutic target. Herein, we describe the current biological understanding of IDH mutations and the roles of mutant IDH in the various associated cancers. We also present the available preclinical and clinical data on various methods of targeting IDH-mutant cancers and discuss, based on the underlying pathogenesis of different IDH-mutated cancer types, whether the treatment approaches will converge or be context dependent.

Automated summary

The article discusses the impact of IDH mutations in various cancers, highlighting the production of oncometabolite and the importance of targeting mutant IDH for therapeutic purposes. It reviews the current understanding and available data on therapeutic strategies for IDH-mutant cancers and speculates on whether treatment approaches will converge or be context dependent based on the underlying pathogenesis.