Abstract Background Rewiring of metabolism induced by oncogenic K-Ras in cancer cells involves both glucose and glutamine utilization sustaining enhanced, unrestricted growth. The development of effective anti-cancer treatments targeting metabolism may be facilitated by the identification and rational combinatorial targeting of metabolic pathways. Methods We performed mass spectrometric metabolomics analysis in vitro and in vivo experiments to evaluate the efficacy of drugs and identify metabolic connectivity. Results We show that K-Ras -mutant lung and colon cancer cells exhibit a distinct metabolic rewiring, the latter being more dependent on respiration. Combined treatment with the glutaminase inhibitor CB-839 and the PI3K/aldolase inhibitor NVP-BKM120 more consistently reduces cell growth of tumor xenografts. Maximal growth inhibition correlates with the disruption of redox homeostasis, involving loss of reduced glutathione regeneration, redox cofactors, and a decreased connectivity among metabolites primarily involved in nucleic acid metabolism. Conclusions Our findings open the way to develop metabolic connectivity profiling as a tool for a selective strategy of combined drug repositioning in precision oncology.

中文翻译：

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代谢连通性分析揭示的 K-Ras 肿瘤中组合药物疗效的氧化还原稳态破坏

摘要背景 癌细胞中由致癌 K-Ras 诱导的代谢重新布线涉及维持增强的、不受限制的生长的葡萄糖和谷氨酰胺利用。代谢途径的识别和合理组合靶向可以促进针对代谢的有效抗癌治疗的开发。方法 我们在体外和体内实验中进行了质谱代谢组学分析，以评估药物的功效并确定代谢连通性。结果我们表明，K-Ras 突变肺癌和结肠癌细胞表现出明显的代谢重新布线，后者更依赖于呼吸。谷氨酰胺酶抑制剂 CB-839 和 PI3K/醛缩酶抑制剂 NVP-BKM120 的联合治疗更一致地减少了肿瘤异种移植物的细胞生长。最大的生长抑制与氧化还原稳态的破坏相关，包括还原型谷胱甘肽再生、氧化还原辅助因子的丧失以及主要参与核酸代谢的代谢物之间的连接性降低。结论 我们的研究结果为开发代谢连通性分析开辟了道路，将其作为一种工具，用于在精准肿瘤学中联合药物重新定位的选择性策略。