Inhibition of Glutaminase Preferentially Slows Growth of Glioma Cells with Mutant IDH1

Mutation at the R132 residue of isocitrate dehydrogenase 1 (IDH1), frequently found in gliomas and acute myelogenous leukemia, creates a neoenzyme that produces 2-hydroxyglutarate (2-HG) from alpha-ketoglutarate (alpha-KG). We sought to therapeutically exploit this neoreaction in mutant IDH1 cells that require alpha-KG derived from glutamine. Glutamine is converted to glutamate by glutaminase and further metabolized to alpha-KG. Therefore, we inhibited glutaminase with siRNA or the small molecule inhibitor bis-2-(5-phenylacetamido-1,2,4- thiadiazol-2-yl) ethyl sulfide (BPTES) and found slowed growth of glioblastoma cells expressing mutant IDH1 compared with those expressing wild-type IDH1. Growth suppression of mutant IDH1 cells by BPTES was rescued by adding exogenous alpha-KG. BPTES inhibited glutaminase activity, lowered glutamate and alpha-KG levels, and increased glycolytic intermediates while leaving total 2-HG levels unaffected. The ability to selectively slow growth in cells with IDH1 mutations by inhibiting glutaminase suggests a unique reprogramming of intermediary metabolism and a potential therapeutic strategy. Cancer Res; 70(22); 8981-7. (C) 2010 AACR.