Journal Article

An Inhibitor of Mutant IDH1 Delays Growth and Promotes Differentiation of Glioma Cells

Grommes, Christian, Komisopoulou, Evangelia, Rosenblum, Marc K., Su, Shinsan M., Silverman, Lee, Pedraza, Alicia, Biller, Scott A., Campos, Carl, Clark, Owen, Schalm, Stefanie, Tsoi, Jennifer, Kunii, Kaiko, Miller, Alexandra, Yang, Hua, Brennan, Cameron W., Kernytsky, Andrew, Oldrini, Barbara, Turcan, Sevin, Palaskas, Nicolaos, Chan, Timothy A., Liu, Wei, Mellinghoff, Ingo K., Wang, Fang, Chen, Yue, Yen, Katharine E., Popovici-Muller, Janeta, Rohle, Dan, Graeber, Thomas G.

2013

Overview

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 (m1DH1) to produce R-2-hydroxyglutarate (R-2HG). Under conditions of near-complete R-2HG inhibition, the m1DH1 inhibitor induced demethylation of histone H3K9me3 and expression of genes associated with gliogenic differentiation. Blockade of m1DH1 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 m1DH1 may promote glioma growth through mechanisms beyond its well-characterized epigenetic effects.

• Publisher: American Association for the Advancement of Science,The American Association for the Advancement of Science
• Subject: Animals / Benzeneacetamides - administration & dosage / Benzeneacetamides - pharmacology / Benzeneacetamides - toxicity / Binding / brain / Brain tumors / Cancer / Cell Differentiation - drug effects / Cell growth / Cell Transformation, Neoplastic / Cells / Cellular differentiation / Delay / Drugs / Enzyme Inhibitors - pharmacology / Enzyme Inhibitors - toxicity / Enzymes / Gene Expression Profiling / Gene Expression Regulation, Neoplastic - drug effects / Genes / Genetic mutation / Glioma / Glioma - drug therapy / Glioma - enzymology / Glioma - genetics / Glioma - pathology / Glutarates - metabolism / Heterologous transplantation / Histones - metabolism / humans / Imidazoles - administration & dosage / Imidazoles - pharmacology / Imidazoles - toxicity / Individualized Instruction / Inhibition / Inhibitors / Isocitrate Dehydrogenase - antagonists & inhibitors / Isocitrate Dehydrogenase - chemistry / Isocitrate Dehydrogenase - genetics / Isocitrate Dehydrogenase - metabolism / Leukemia / Methylation / Mice / Mice, SCID / Mutant Proteins - antagonists & inhibitors / Mutant Proteins - chemistry / Mutant Proteins - metabolism / Mutants / Mutation / Mutations / neoplasm cells / neoplasms / Neurons / Online / Protein Multimerization / RNA / RNA Interference / Tumors / Xenograft Model Antitumor Assays