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.

• Authors: Dan Rohle, Janeta Popovici-Muller, Nicolaos Palaskas, Sevin Turcan, Christian Grommes, Carl Campos, Jennifer Tsoi, Owen Clark, Barbara Oldrini, Evangelia Komisopoulou, Kaiko Kunii, Alicia Pedraza, Stefanie Schalm, Lee Silverman, Alexandra Miller, Fang Wang, Hua Yang, Yue Chen, Andrew Kernytsky, Marc K Rosenblum, Wei Liu, Scott A Biller, Shinsan M Su, Cameron W Brennan, Timothy A Chan, Thomas G Graeber, Katharine E Yen, Ingo K Mellinghoff
• Journal: Science (New York, N.Y.) (Science) Vol. 340 Issue 6132 Pg. 626-30 (May 03 2013) ISSN: 1095-9203 [Electronic] United States
• PMID: 23558169 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• AGI-5198
• Benzeneacetamides
• Enzyme Inhibitors
• Glutarates
• Histones
• Imidazoles
• Mutant Proteins
• alpha-hydroxyglutarate
• Isocitrate Dehydrogenase
• IDH1 protein, human

Topics

• Animals
• Benzeneacetamides (administration & dosage, pharmacology, toxicity)
• Cell Differentiation (drug effects)
• Cell Transformation, Neoplastic
• Enzyme Inhibitors (pharmacology, toxicity)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (drug effects)
• Glioma (drug therapy, enzymology, genetics, pathology)
• Glutarates (metabolism)
• Histones (metabolism)
• Imidazoles (administration & dosage, pharmacology, toxicity)
• Isocitrate Dehydrogenase (antagonists & inhibitors, chemistry, genetics, metabolism)
• Methylation
• Mice
• Mice, SCID
• Mutant Proteins (antagonists & inhibitors, chemistry, metabolism)
• Protein Multimerization
• RNA Interference
• Xenograft Model Antitumor Assays