Understanding how carcinogenesis can expose cancers to synthetically lethal vulnerabilities has been an essential underpinning of development of modern anticancer therapeutics. Isocitrate dehydrogenase wild-type (IDHWT) glioblastoma multiforme (GBM), which is known to have upregulated branched-chain amino acid transaminase 1 (BCAT1) expression, has not had treatments developed to the same extent as the IDH mutant counterpart, despite making up the majority of cases. In this issue, Zhang and colleagues utilize a metabolic screen to identify α-ketoglutarate (AKG) as a synthetically lethal treatment in conjunction with BCAT1 inhibition in IDHWT GBM. These treatments synergize in a multipronged approach that limits substrate catabolism and disrupts mitochondrial homeostasis through perturbing the balance of NAD+/NADH, leading to mTORC1 inhibition and a reduction of nucleotide biosynthesis. Based on these results, the authors propose combination treatment targeting branched chain amino acid catabolism as a potential option for patients with IDHWT GBM. See related article by Zhang et al., p. 2388

中文翻译：

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双脚驱动：补充 AKG 同时抑制 BCAT1 导致 GBM 综合致死

了解致癌作用如何使癌症暴露于综合致命的脆弱性一直是现代抗癌疗法发展的重要基础。异柠檬酸脱氢酶野生型 (IDHWT) 多形性胶质母细胞瘤 (GBM) 已知上调支链氨基酸转氨酶 1 (BCAT1) 表达，但尚未开发出与 IDH 突变体对应物相同程度的治疗方法，尽管大多数情况下。在本期中，Zhang 及其同事利用代谢筛选将 α-酮戊二酸 (AKG) 鉴定为与 IDHWT GBM 中的 BCAT1 抑制相结合的综合致死治疗方法。这些治疗以多管齐下的方式协同作用，通过扰乱 NAD+/NADH 的平衡来限制底物分解代谢并破坏线粒体稳态，导致 mTORC1 抑制和核苷酸生物合成减少。基于这些结果，作者提出针对支链氨基酸分解代谢的联合治疗作为 IDHWT GBM 患者的潜在选择。参见Zhang 等人的相关文章，第 17 页。2388