| First Author | Rohle D | Year | 2013 |
| Journal | Science | Volume | 340 |
| Issue | 6132 | Pages | 626-30 |
| PubMed ID | 23558169 | Mgi Jnum | J:198193 |
| Mgi Id | MGI:5495844 | Doi | 10.1126/science.1236062 |
| Citation | Rohle D, et al. (2013) An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science 340(6132):626-30 |
| abstractText | 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. |
