Targeting BCAT1 Combined with a-Ketoglutarate Triggers Metabolic Synthetic Lethality in Glioblastoma

Branched-chain amino acid transaminase 1 (BCAT1) is upregulated selectively in human isocitrate dehydrogenase (IDH) wildtype (WT) but not mutant glioblastoma multiforme (GBM) and promotes IDH^WT GBM growth. Through a metabolic synthetic lethal screen, we report here that a-ketoglutarate (AKG) kills IDH^WT GBM cells when BCAT1 protein is lost, which is reversed by reexpression of BCAT1 or supplementation with branched-chain a-ketoacids (BCKA), downstream metabolic products of BCAT1. In patient-derived IDH^WT GBM tumors in vitro and in vivo, cotreatment of BCAT1 inhibitor gabapentin and AKG resulted in synthetic lethality. However, AKG failed to evoke a synthetic lethal effect with loss of BCAT2, BCKDHA, or GPT2 in IDH^WT GBM cells. Mechanistically, loss of BCAT1 increased the NAD^þ/NADH ratio but impaired oxidative phosphorylation, mTORC1 activity, and nucleotide biosynthesis. These metabolic alterations were synergistically augmented by AKG treatment, thereby causing mitochondrial dysfunction and depletion of cellular building blocks, including ATP, nucleotides, and proteins. Partial restoration of ATP, nucleotides, proteins, and mTORC1 activity by BCKA supplementation prevented IDH^WT GBM cell death conferred by the combination of BCAT1 loss and AKG. These findings define a targetable metabolic vulnerability in the most common subset of GBM that is currently incurable. Significance: Metabolic synthetic lethal screening in IDH^WT glioblastoma defines a vulnerability to AKG following BCAT1 loss, uncovering a therapeutic strategy to improve glioblastoma treatment.