Title | An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. |
Publication Type | Journal Article |
Year of Publication | 2013 |
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 MK, Liu W, Biller SA, Su SM, Brennan CW, Chan TA, Graeber TG, Yen KE, Mellinghoff IK |
Journal | Science |
Volume | 340 |
Issue | 6132 |
Pagination | 626-30 |
Date Published | 2013 May 03 |
ISSN | 1095-9203 |
Keywords | Animals, Benzeneacetamides, Cell Differentiation, Cell Transformation, Neoplastic, Enzyme Inhibitors, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Glioma, Glutarates, Histones, Imidazoles, Isocitrate Dehydrogenase, Methylation, Mice, Mice, SCID, Mutant Proteins, Protein Multimerization, RNA Interference, Xenograft Model Antitumor Assays |
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. |
DOI | 10.1126/science.1236062 |
Alternate Journal | Science |
PubMed ID | 23558169 |
PubMed Central ID | PMC3985613 |
Grant List | T32 CA160001 / CA / NCI NIH HHS / United States U54 CA143798 / CA / NCI NIH HHS / United States 1R01NS080944-01 / NS / NINDS NIH HHS / United States P30 CA008748 / CA / NCI NIH HHS / United States R01 NS080944 / NS / NINDS NIH HHS / United States U54CA143798 / CA / NCI NIH HHS / United States |
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