Background Targeting glutamine metabolism in cancer has become an increasingly vibrant area of research. Mutant IDH1 (IDH1 mut ) gliomas are considered good candidates for targeting this pathway because of the contribution of glutamine to their newly acquired function: synthesis of 2-hydroxyglutarate (2HG). Methods We have employed a combination of 13 C tracers including glutamine and glucose for investigating the metabolism of patient-derived IDH1 mut glioma cell lines through NMR and LC/MS. Additionally, genetic loss-of-function (in vitro and in vivo) approaches were performed to unravel the adaptability of these cell lines to the inhibition of glutaminase activity. Results We report the adaptability of IDH1 mut cells’ metabolism to the inhibition of glutamine/glutamate pathway. The glutaminase inhibitor CB839 generated a decrease in the production of the downstream metabolites of glutamate, including those involved in the TCA cycle and 2HG. However, this effect on metabolism was not extended to viability; rather, our patient-derived IDH1 mut cell lines display a metabolic plasticity that allows them to overcome glutaminase inhibition. Conclusions Major metabolic adaptations involved pathways that can generate glutamate by using alternative substrates from glutamine, such as alanine or aspartate. Indeed, asparagine synthetase was upregulated both in vivo and in vitro revealing a new potential therapeutic target for a combinatory approach with CB839 against IDH1 mut gliomas.

中文翻译：

---

IDH1突变神经胶质瘤细胞系的代谢可塑性导致对谷氨酰胺酶抑制的敏感性低

背景 针对癌症中的谷氨酰胺代谢已成为一个日益活跃的研究领域。突变 IDH1 (IDH1 mut ) 胶质瘤被认为是靶向该途径的良好候选者，因为谷氨酰胺对其新获得的功能的贡献：2-羟基戊二酸 (2HG) 的合成。方法 我们采用了包括谷氨酰胺和葡萄糖在内的 13 C 示踪剂的组合，通过 NMR 和 LC/MS 研究患者来源的 IDH1 mut 胶质瘤细胞系的代谢。此外，还进行了遗传功能丧失（体外和体内）方法，以揭示这些细胞系对抑制谷氨酰胺酶活性的适应性。结果 我们报告了 IDH1 mut 细胞代谢对抑制谷氨酰胺/谷氨酸途径的适应性。谷氨酰胺酶抑制剂 CB839 减少了谷氨酸下游代谢物的产生，包括那些参与 TCA 循环和 2HG 的代谢物。然而，这种对新陈代谢的影响并没有扩展到生存能力；相反，我们的患者来源的 IDH1 mut 细胞系表现出代谢可塑性，使它们能够克服谷氨酰胺酶抑制。结论 主要的代谢适应涉及可以通过使用来自谷氨酰胺的替代底物（例如丙氨酸或天冬氨酸）产生谷氨酸的途径。事实上，天冬酰胺合成酶在体内和体外都被上调，揭示了与 CB839 联合治疗 IDH1 mut 神经胶质瘤的新潜在治疗靶点。这种对新陈代谢的影响并未扩展到生存能力；相反，我们的患者来源的 IDH1 mut 细胞系表现出代谢可塑性，使它们能够克服谷氨酰胺酶抑制。结论 主要的代谢适应涉及可以通过使用来自谷氨酰胺的替代底物（例如丙氨酸或天冬氨酸）产生谷氨酸的途径。事实上，天冬酰胺合成酶在体内和体外都被上调，揭示了与 CB839 联合治疗 IDH1 mut 神经胶质瘤的新潜在治疗靶点。这种对新陈代谢的影响并未扩展到生存能力；相反，我们的患者来源的 IDH1 mut 细胞系表现出代谢可塑性，使它们能够克服谷氨酰胺酶抑制。结论 主要的代谢适应涉及可以通过使用来自谷氨酰胺的替代底物（例如丙氨酸或天冬氨酸）产生谷氨酸的途径。事实上，天冬酰胺合成酶在体内和体外都被上调，揭示了与 CB839 联合治疗 IDH1 mut 神经胶质瘤的新潜在治疗靶点。