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.
Mutations in IDH1 or IDH2 are frequent among several cancer types with various tissues of origin; the resultant mutated enzymes have neomorphic activity that leads to production of the oncometabolite D-2-hydroxyglutarate (D-2HG), which has profound effects on cellular epigenetic programmes, differentiation patterns and metabolic profiles.
The high prevalence of the IDH hotspot mutations, their occurrence early in tumorigenesis and the resulting uniform expression of the mutated protein in tumour cells make mutant isocitrate dehydrogenase (IDH) an appealing therapeutic target.
The roles of mutant IDH1 and IDH2 in cancer development and progression are probably transient or dynamic and context dependent.
IDH mutation status at disease recurrence can provide insights into their overall pathogenic role. In acute myeloid leukaemia, resistance mutations that restore the generation of D-2HG arise in response to inhibition of mutant IDH1 or IDH2, whereas recurrent gliomas often have a loss of heterozygosity of the affected IDH gene and decreased D-2HG production.
The greater efficacy of mutant IDH inhibitors against non-enhancing gliomas suggests that the timing of treatment with such agents is of crucial importance.
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The work of C.J.P. has been supported by the Hope Funds for Cancer Research. The authors thank L. Chen, P. K. Greer, N. M. Reynolds and K. Brooks Roso, of Duke University, for critical editorial review, support and guidance with data representation.
H.Y. is the chief scientific officer and has ownership interest in Genetron Holdings and receives royalties from Agios, Genetron and Personal Genome Diagnostics (PGDX). H.Y. holds a patent related to genetic alterations in IDH and other genes in malignant glioma (US Patent 8,685,660B2) issued, licensed and with royalties paid by Agios; a patent for genetic alterations in IDH and other genes in malignant glioma issued, licensed and with royalties paid by PGDX; a patent on methods for the rapid and sensitive detection of hotspot mutations (US 10,633,711B2) issued, licensed and with royalties paid by Genetron Holdings; a patent on homozygous and heterozygous IDH1 gene-defective human astrocytoma cell lines (US 9,695,400B2); and a patent on homozygous and heterozygous IDH1 gene-defective cell lines derived from human colorectal cells (US 9,074,221B2). C.J.P. declares no competing interests.
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Pirozzi, C.J., Yan, H. The implications of IDH mutations for cancer development and therapy. Nat Rev Clin Oncol 18, 645–661 (2021). https://doi.org/10.1038/s41571-021-00521-0
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