Isocitrate Dehydrogenase Mutations in Cancer Metabolism

Somatic mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) underpin a distinct oncogenic programme characterised by the neomorphic conversion of α-ketoglutarate into the oncometabolite D-2-hydroxyglutarate. This aberrant enzymatic activity precipitates widespread epigenetic remodelling, notably DNA and histone hypermethylation, and perturbs redox homeostasis by diverting NADPH pools. The resultant metabolic rewiring fosters blocks in differentiation, creates specific vulnerabilities in central carbon metabolism and sensitises tumours to tailored small-molecule inhibitors. Structural and kinetic studies have elucidated active-site alterations across mutant alleles, enabling the rational design of selective inhibitors. Concurrently, insights into subcellular compartmentalisation and synthetic lethality strategies are broadening therapeutic horizons. Together, these advances are rapidly translating into precision-medicine approaches for glioma, acute myeloid leukaemia and other IDH-mutant cancers worldwide.

Research from Nature Portfolio

Active-site remodelling in IDH1 R132Q versus R132H mutants has been probed through combined static and dynamic structural methods, revealing conformations optimised for both conventional and neomorphic activities and identifying residues critical for next-generation inhibitor selectivity and resistance avoidance. An investigation into mutant IDH1/2-derived D-2-hydroxyglutarate demonstrated that this oncometabolite directly activates mTOR signalling by inhibiting the αKG-dependent demethylase KDM4A, thus linking TCA-cycle defects to a major growth pathway. Further work has established that IDH1-mutant glioma cells, owing to 2-hydroxyglutarate-mediated depletion of ATP and suppression of mTOR-driven synthesis, exhibit pronounced sensitivity to Bcl-xL inhibition, uncovering a synthetic-lethality axis with potential for durable therapeutic responses.

Isocitrate Dehydrogenase Mutations in Cancer Metabolism publication trend

The graph below shows the total number of articles in isocitrate dehydrogenase mutations in cancer metabolism across all publications each year (not limited to Nature Index journals).

Technical terms

Neomorphic activity: A novel enzymatic function acquired by a mutant protein that is absent in the wild-type form.

Oncometabolite: A metabolite whose aberrant accumulation promotes tumourigenesis by altering cellular signalling or epigenetic regulation.

D-2-hydroxyglutarate: The chiral oncometabolite produced by mutant IDH1/2 that competitively inhibits αKG-dependent dioxygenases.

Synthetic lethality: A cellular state in which simultaneous perturbation of two genes or pathways leads to cell death, whereas disruption of either alone is tolerated.

Inhibitor residence time: The duration for which a small-molecule inhibitor remains bound to its target enzyme under physiological conditions.

References

1. Active site remodeling in tumor-relevant IDH1 mutants drives distinct kinetic features and potential resistance mechanisms. Nature Communications (2024).
2. Electrochemical Nanoreactor Provides a Comprehensive View of Isocitrate Dehydrogenase Cancer‐drug Kinetics. Angewandte Chemie International Edition (2023).
3. IDH mutation in glioma: molecular mechanisms and potential therapeutic targets. British Journal of Cancer (2020).
4. The Potential for Isocitrate Dehydrogenase Mutations to Produce 2-Hydroxyglutarate Depends on Allele Specificity and Subcellular Compartmentalization*. Journal of Biological Chemistry (2012).
5. Mutant Isocitrate Dehydrogenase Inhibitors as Targeted Cancer Therapeutics. Frontiers in Oncology (2019).
6. The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway. Nature Communications (2016).
7. Induction of synthetic lethality in IDH1-mutated gliomas through inhibition of Bcl-xL. Nature Communications (2017).