An Inhibitor of Mutant IDH1 Delays Growth and Promotes Differentiation of Glioma Cells
IDHology Among the most exciting drug targets to emerge from cancer genome sequencing projects are two related metabolic enzymes, isocitrate dehydrogenases 1 and 2 (IDH1, IDH2) Mutations in the IDH1 and IDH2 genes are common in certain types of human cancer. Whether inhibition of mutant IDH activity might offer therapeutic benefits is unclear (see the Perspective by Kim and DeBerardinis) F. Wang et al. (p. 622, published online 4 April) isolated a small molecule that selectively inhibits mutant IDH2, describe the structural details of its binding to the mutant enzyme, and show that this compound suppresses the growth of patient derived leukemia cells harboring the IDH2 mutation. Rohle et al. (p. 626, published online 4 April) show that a small molecule inhibitor of IDH1 selectively slows the growth of patient derived brain tumor cells with the IDH1 mutation. A small molecule that inhibits a mutant enzyme in tumors slows malignant growth by inducing cancer cell differentiation. [Also see Perspective by Kim and DeBerardinis] 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.
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