IDH mutation in glioma: molecular mechanisms and potential therapeutic targets

Abstract

Isocitrate dehydrogenase (IDH) enzymes catalyse the oxidative decarboxylation of isocitrate and therefore play key roles in the Krebs cycle and cellular homoeostasis. Major advances in cancer genetics over the past decade have revealed that the genes encoding IDHs are frequently mutated in a variety of human malignancies, including gliomas, acute myeloid leukaemia, cholangiocarcinoma, chondrosarcoma and thyroid carcinoma. A series of seminal studies further elucidated the biological impact of the IDH mutation and uncovered the potential role of IDH mutants in oncogenesis. Notably, the neomorphic activity of the IDH mutants establishes distinctive patterns in cancer metabolism, epigenetic shift and therapy resistance. Novel molecular targeting approaches have been developed to improve the efficacy of therapeutics against IDH-mutated cancers. Here we provide an overview of the latest findings in IDH-mutated human malignancies, with a focus on glioma, discussing unique biological signatures and proceedings in translational research.

Fig. 1. Dimerisation of IDH1.

Two wild-type IDH1 monomers form a catalytic homodimer, which transforms isocitrate into α-KG. In IDH1-mutated cells, a catalytic heterodimer is formed with one wild-type monomer and one monomer carrying the R132H mutant. The heterodimer exhibits neomorphic activity, which consumes α-KG for D-2-HG synthesis. Biochemical studies indicate that a homodimer formed by two IDH1 mutant monomer is not catalytically active. Molecular modelling is based on the published crystal structures 1T09, 3MAS and 3MAP.

Fig. 2. Metabolic reprogramming in IDH1-mutated glioma.

Acquisition of IDH mutant results in substantial metabolic reprogramming. Neomorphic activity depletes the Krebs cycle by exhausting α-KG for D-2-HG production. Metabolites such as glutamine, glutamate and branched-chain amino acids (BCAA) serve as compensatory sources to fuel cellular metabolism. D-2-HG further impacts cellular metabolism such as the biosynthesis of glutamate and NAD. D-2-HG affects the biological function of PHD2, whereas the alterations in hypoxia-sensing pathway remain unclear.

Fig. 3. IDH1 mutants result in alterations throughout the epigenome.

Owing to structural similarity, IDH1-mutant-derived D-2-HG serves as a competitive inhibitor for KDM4 or TET and therefore blocks the demethylation process in histone and nucleotide, respectively.

Fig. 4. IDH mutants disrupt redox homoeostasis.

The neomorphic activity of IDH1 mutant consumes NADPH for NADP⁺ production, which suppresses the detoxification of H₂O₂. Nrf2-associated gene transcription, such as glutamate-cysteine ligase (GLS), supports glutathione de novo synthesis. Amino acids such as glutamine, glutamate, cysteine and glycine are utilised for glutathione synthesis, which serves as an alternative metabolic support for ROS detoxification.