IDH Mutations as a Therapeutic Target Across Multiple Cancer Types
IDH1/2 mutations occur in 20-80% of AML, cholangiocarcinoma, chondrosarcoma, and glioma, producing the oncometabolite D-2-hydroxyglutarate. The review details how these neomorphic mutations represent an ideal diagnostic and therapeutic target, with direct implications for clinical labs performing IDH mutation testing by NGS, PCR, or immunohistochemistry as part of standard oncology workups.
The original study
The implications of IDH mutations for cancer development and therapy.
- Authors
- Pirozzi CJ, Yan H
- Journal
- Nature reviews. Clinical oncology
- Type
- Journal Article, Research Support, Non-U.S. Gov't, Review
- PMID
- 34131315
Original abstract
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.