An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells Journal Article
| Authors: | Rohle, D.; Popovici-Muller, J.; Palaskas, N.; Turcan, S.; Grommes, C.; Campos, C.; Tsoi, J.; Clark, O.; Oldrini, B.; Komisopoulou, E.; Kunii, K.; Pedraza, A.; Schalm, S.; Silverman, L.; Miller, A.; Wang, F.; Yang, H.; Chen, Y.; Kernytsky, A.; Rosenblum, M. K.; Liu, W.; Biller, S. A.; Su, S. M.; Brennan, C. W.; Chan, T. A.; Graeber, T. G.; Yen, K. E.; Mellinghoff, I. K. |
| Article Title: | An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells |
| 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. |
| Journal Title: | Science |
| Volume: | 340 |
| Issue: | 6132 |
| ISSN: | 0036-8075 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 2013-05-03 |
| Start Page: | 626 |
| End Page: | 630 |
| Language: | English |
| DOI: | 10.1126/science.1236062 |
| PROVIDER: | scopus |
| PUBMED: | 23558169 |
| PMCID: | PMC3985613 |
| DOI/URL: | |
| Notes: | --- - Cited By (since 1996):2 - "Export Date: 3 June 2013" - "CODEN: SCIEA" - "Source: Scopus" |
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