Biological Role and Therapeutic Potential of IDH Mutations in Cancer

Abstract

Hotspot mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) occur in a variety of myeloid malignancies and solid tumors. Mutant IDH proteins acquire a neomorphic enzyme activity to produce the putative oncometabolite D-2-hydroxyglutarate, which is thought to block cellular differentiation by competitively inhibiting α-ketoglutarate-dependent dioxygenases involved in histone and DNA demethylation. Small-molecule inhibitors of mutant IDH1 and IDH2 have been developed and are progressing through pre-clinical and clinical development. In this review, we provide an overview of mutant IDH-targeted therapy and discuss a number of important recent pre-clinical studies using models of IDH-mutant solid tumors.

Keywords: 2-hydroxyglutarate; acute myeloid leukemia; cancer therapy; glioblastoma; glioma; isocitrate dehydrogenase.

Figure 1. Potential Therapeutic Strategies for Malignancies that Harbor IDH1 or IDH2 Mutations

A number of pharmacological inhibitors have been developed to directly inhibit the neomorphic activity of mutant IDH enzymes in an effort to reduce D2HG production and elicit differentiation of malignant progenitor cells. Alternatively, inhibitors of enzymes involved in glutaminolysis, including glutamate dehydrogenases and glutaminase, have been shown to preferentially inhibit the growth of leukemia and glioma cells with IDH mutations. Similarly, NAMPT inhibitors are proposed to exploit the observation that NAPRT1-mediated conversion of nicotinic acid to NAD⁺ is defective in IDH mutant gliomas (indicated by an X in the figure). Hypomethylating agents such as azacytidine and decitibine may also promote differentiation of IDH mutant cells, which exhibit a hypermethylation phenotype that is associated with an inhibition of differentiation. Co-occurring driver alterations, such as MYCN amplification, may be targeted in IDH mutant tumors using available targeted therapies (e.g. JQ1 for n-Myc overexpression) in a tumor-specific manner.