Abstract
BCAT inactivation renders IDH-mutant cells dependent on glutaminase for glutamate and glutathione synthesis.
Major finding: BCAT inactivation renders IDH-mutant cells dependent on glutaminase for glutamate and glutathione synthesis.
Concept: IDH mutations are synthetic lethal with glutaminase inhibition under conditions of oxidative stress.
Impact: IDH-mutant gliomas may be sensitive to glutaminase inhibition in combination with radiotherapy.
Mutations in IDH1 occur frequently in patients with glioma and result in accumulation of the oncometabolite (R)-2HG, which has been shown to inhibit 2OG-dependent dioxygenases including JmjC histone demethylases and TET DNA hydroxylases. In addition to dioxygenases, cells have other 2OG-dependent enzymes, including transaminases. It was previously reported that conditioned media from IDH-mutant cells has reduced levels of branched chain α-ketoacids, which are generated from branched chain amino acids (BCAA) by the BCAA transaminases BCAT1 and BCAT2. This finding prompted McBrayer and colleagues to hypothesize that (R)-2HG might inhibit BCAT activity and create targetable metabolic vulnerabilities in IDH-mutant tumors. Indeed, (R)-2HG directly inhibited BCAT1 and BCAT2. Thus, mutant IDH inhibited BCAA transamination to suppress glutamate biosynthesis, and BCAT inhibition induced a compensatory increase in glutamine-dependent glutamate synthesis. In vivo, IDH-mutant gliomas exhibited decreased levels of glutamate, consistent with decreased BCAT-dependent glutamate synthesis. BCAT inhibition–mediated glutamate depletion decreased glutathione levels, thereby rendering IDH-mutant glioma cells hyperdependent on glutaminase for glutamate and glutathione synthesis. Consistent with these findings, glutaminase inhibition was synthetic lethal with IDH mutations under conditions of oxidative stress, depleting glutamate and reducing glutathione levels to induce cell death. Thus, glutaminase inhibition rendered IDH-mutant gliomas sensitive to radiation-induced cytotoxicity. Taken together, these findings demonstrate that (R)-2HG inhibits BCAT1 and BCAT2 in IDH-mutant glioma and uncover a synthetic lethal relationship between IDH mutations and glutaminase inhibition under oxidative stress that may be exploited therapeutically by combining radiotherapy with glutaminase inhibitors in patients with IDH-mutant tumors.
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