Editors' ChoiceCancer

It takes two to tango: IDH mutation and glutaminase inhibition in glioma

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Science Translational Medicine  26 Sep 2018:
Vol. 10, Issue 460, eaav0344
DOI: 10.1126/scitranslmed.aav0344

Abstract

IDH1 mutant gliomas show increased radiation sensitivity in combination with a glutaminase inhibitor.

Isocitrate dehydrogenase (IDH) enzymes are frequently mutated in human cancers, including gliomas and leukemias. Inhibitors of mutant IDH enzymes have been shown to benefit leukemia patients, as evidenced by recent U.S. Food and Drug Administration (FDA) approval of the IDH2 inhibitor enasidenib to treat acute myeloid leukemia (AML). However, such drugs have not yet shown consistent efficacy in brain tumors, highlighting the importance of identifying therapeutic vulnerabilities for IDH1 mutant gliomas.

IDH mutations lead to production of the oncometabolite (R)-2-hydroxyglutarate [(R)-2HG], which inhibits 2OG-dependent dioxygenases. Surprisingly, McBrayer et al. found that (R)-2HG can also inhibit BCAT1 and BCAT2, two members of the 2OG-dependent transaminase enzyme family that make important contributions to cellular glutamate synthesis. As a result of decreased BCAT activity, IDH1 mutant glioma cells display increased reliance on glutaminase activity for glutamate and glutathione synthesis. Glutathione protects cells from damage caused by the reactive oxygen species (ROS) generated during oxidative stress or radiation therapy. Treating IDH mutant glioma cells with the glutaminase inhibitor CB-839 suppressed glutamate and glutathione production and increased susceptibility of these cells to ROS-induced cell death. As predicted by this model, xenograft tumors established from IDH1 mutant glioma cells—but not their IDH1 wild-type counterparts—demonstrated enhanced radiation therapy sensitivity when combined with CB-839, leading to prolonged survival of mice bearing these tumors.

Overall, this important research reveals a novel synthetic lethality interaction between IDH1 mutation and glutaminase inhibition in glioma that selectively manifests under conditions of oxidative stress. This finding has motivated an upcoming clinical trial (NCT03528642) to test the combination of radiation, the chemotherapy drug temozolomide, and glutaminase inhibitor therapies for the treatment of IDH1 mutant astrocytoma. Further investigation should test this therapeutic strategy in additional preclinical glioma models, particularly patient-derived xenograft models. Furthermore, as mentioned in the study, the modest ability of CB-839 to cross the blood-brain barrier may limit efficacy in the clinic. If such a limitation is encountered, the study by McBrayer et al. provides strong motivation for the development of glutaminase inhibitors with greater brain penetrance that may be better suited for glioma therapy.

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