Department of Pathology, UT Southwestern Medical Center, Dallas, Texas.
Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, Texas.
Cancer Res. 2022 Jul 5;82(13):2388-2402. doi: 10.1158/0008-5472.CAN-21-3868.
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 IDHWT GBM growth. Through a metabolic synthetic lethal screen, we report here that α-ketoglutarate (AKG) kills IDHWT GBM cells when BCAT1 protein is lost, which is reversed by reexpression of BCAT1 or supplementation with branched-chain α-ketoacids (BCKA), downstream metabolic products of BCAT1. In patient-derived IDHWT 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 IDHWT GBM cells. Mechanistically, loss of BCAT1 increased the NAD+/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 IDHWT 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.
Metabolic synthetic lethal screening in IDHWT glioblastoma defines a vulnerability to ΑΚG following BCAT1 loss, uncovering a therapeutic strategy to improve glioblastoma treatment. See related commentary by Meurs and Nagrath, p. 2354.
支链氨基酸转氨酶 1（BCAT1）在人类异柠檬酸脱氢酶（IDH）野生型（WT）中选择性上调，但在突变型多形性胶质母细胞瘤（GBM）中不上调，并促进 IDHWT GBM 的生长。通过代谢合成致死筛选，我们在此报告，当 BCAT1 蛋白丢失时，α-酮戊二酸（AKG）会杀死 IDHWT GBM 细胞，而当重新表达 BCAT1 或补充支链α-酮酸（BCKA）（BCAT1 的下游代谢产物）时，这种情况会逆转。在体外和体内患者来源的 IDHWT GBM 肿瘤中，BCAT1 抑制剂加巴喷丁和 AKG 的联合治疗导致合成致死。然而，在 IDHWT GBM 细胞中，当 BCAT2、BCKDHA 或 GPT2 缺失时，AKG 未能引起合成致死效应。从机制上讲，BCAT1 的缺失增加了 NAD+/NADH 比率，但损害了氧化磷酸化、mTORC1 活性和核苷酸合成。AKG 处理进一步增强了这些代谢改变，从而导致线粒体功能障碍和细胞构建块（包括 ATP、核苷酸和蛋白质）耗竭。BCKA 补充部分恢复了 ATP、核苷酸、蛋白质和 mTORC1 活性，从而阻止了由 BCAT1 缺失和 AKG 联合作用引起的 IDHWT GBM 细胞死亡。这些发现定义了目前无法治愈的最常见 GBM 亚群的可靶向代谢脆弱性。
在 IDHWT 胶质母细胞瘤中进行代谢合成致死筛选，确定了在 BCAT1 缺失后对 ΑΚG 的易感性，揭示了改善胶质母细胞瘤治疗的治疗策略。见 Meurs 和 Nagrath 的相关评论，第 2354 页。
