An Inhibitor of Mutant IDH1 Delays Growth and Promotes Differentiation of Glioma Cells

TLDR

Mutations in metabolic enzymes, particularly IDH1, have renewed interest in targeting altered cancer metabolism. The study investigates the role of mutant IDH1 in fully transformed cells that harbor endogenous IDH1 mutations. A high‑throughput screen identified AGI‑5198, a selective inhibitor that dose‑dependently blocks mutant IDH1’s production of R‑2‑hydroxyglutarate. Near‑complete R‑2HG inhibition by AGI‑5198 induced histone demethylation, upregulated gliogenic genes, and selectively impaired growth of IDH1‑mutant glioma cells without altering global DNA methylation, indicating that mIDH1 promotes glioma growth through non‑epigenetic mechanisms.

Abstract

The recent discovery of mutations in metabolic enzymes has rekindled interest in harnessing the altered metabolism of cancer cells for cancer therapy. One potential drug target is isocitrate dehydrogenase 1 (IDH1), which is mutated in multiple human cancers. Here, we examine the role of mutant IDH1 in fully transformed cells with endogenous IDH1 mutations. A selective R132H-IDH1 inhibitor (AGI-5198) identified through a high-throughput screen blocked, in a dose-dependent manner, the ability of the mutant enzyme (mIDH1) to produce R-2-hydroxyglutarate (R-2HG). Under conditions of near-complete R-2HG inhibition, the mIDH1 inhibitor induced demethylation of histone H3K9me3 and expression of genes associated with gliogenic differentiation. Blockade of mIDH1 impaired the growth of IDH1-mutant--but not IDH1-wild-type--glioma cells without appreciable changes in genome-wide DNA methylation. These data suggest that mIDH1 may promote glioma growth through mechanisms beyond its well-characterized epigenetic effects.