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

摘要

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 (mlDH1) to produce R-2-hydroxyglutarate (R-2HG). Under conditions of near-complete R-2HG inhibition, the mlDHl inhibitor induced demethylation of histone H3K9me3 and expression of genes associated with gliogenic differentiation. Blockade of mlDHl impaired the growth of IDW1-mutant-but not IDW1-wild-type-glioma cells without appreciable changes in genome-wide DNA methylation. These data suggest that mlDHl may promote glioma growth through mechanisms beyond its well-characterized epigenetic effects.