The glutamine antagonist prodrug JHU-083 slows malignant glioma growth and disrupts mTOR signaling.
The glutamine antagonist prodrug JHU-083 slows malignant glioma growth and disrupts mTOR signaling.
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DOI：
10.1093/noajnl/vdaa149
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发表时间：
2021-01
期刊：
影响因子：
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通讯作者：
Riggins GJ
中科院分区：
文献类型：
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作者：
Yamashita AS;da Costa Rosa M;Stumpo V;Rais R;Slusher BS;Riggins GJ
代谢重编程是癌症的常见特征，对促进癌细胞生长至关重要。异柠檬酸脱氢酶1/2(IDH1和IDH2)突变(IDHmut)是II、III级胶质瘤和继发性胶质母细胞瘤中最常见的基因改变，这些突变增加了对谷氨酰胺代谢的依赖，提示了潜在的脆弱性。在这项研究中，我们验证了脑穿透性谷氨酰胺拮抗剂前药JHU-083抑制胶质瘤细胞生长的假设。我们对谷氨酰胺缺失或谷氨酰胺酶(GLS)基因沉默的胶质瘤细胞进行了细胞生长、细胞周期和蛋白表达的研究。我们检测了JHU-083对癌细胞株的细胞增殖、代谢和mTOR信号转导的影响。采用原位IDH1R132H脑胶质瘤模型，检测JHU-083的体内药效。谷氨酰胺剥夺和GLS基因沉默抑制了胶质瘤细胞的体外增殖。JHU-083通过不依赖于TSC2调控和谷氨酰胺降解的机制，抑制胶质瘤细胞的生长，调节细胞代谢，干扰mTOR信号转导，下调Cyclin D1蛋白表达。IDH1R132H等基因细胞优先抑制细胞生长和mTOR信号下调。此外，补充鸟嘌呤在体外部分挽救了IDHmut胶质瘤细胞的生长、mTOR信号转导和Cyclin D1蛋白的表达。最后，JHU-083延长了脑内IDH1 MUT胶质瘤模型的存活时间，并减少了脑内pS6蛋白的表达。靶向谷氨酰胺代谢的JHU-083在IDHmut胶质瘤的临床前模型中显示出有效性，并显著减少了mTOR信号转导。
Metabolic reprogramming is a common feature in cancer, and it is critical to facilitate cancer cell growth. Isocitrate Dehydrogenase 1/2 (IDH1 and IDH2) mutations (IDHmut) are the most common genetic alteration in glioma grade II and III and secondary glioblastoma and these mutations increase reliance on glutamine metabolism, suggesting a potential vulnerability. In this study, we tested the hypothesis that the brain penetrant glutamine antagonist prodrug JHU-083 reduces glioma cell growth. We performed cell growth, cell cycle, and protein expression in glutamine deprived or Glutaminase (GLS) gene silenced glioma cells. We tested the effect of JHU-083 on cell proliferation, metabolism, and mTOR signaling in cancer cell lines. An orthotopic IDH1R132H glioma model was used to test the efficacy of JHU-083 in vivo. Glutamine deprivation and GLS gene silencing reduced glioma cell proliferation in vitro in glioma cells. JHU-083 reduced glioma cell growth in vitro, modulated cell metabolism, and disrupted mTOR signaling and downregulated Cyclin D1 protein expression, through a mechanism independent of TSC2 modulation and glutaminolysis. IDH1R132H isogenic cells preferentially reduced cell growth and mTOR signaling downregulation. In addition, guanine supplementation partially rescued IDHmut glioma cell growth, mTOR signaling, and Cyclin D1 protein expression in vitro. Finally, JHU-083 extended survival in an intracranial IDH1 mut glioma model and reduced intracranial pS6 protein expression. Targeting glutamine metabolism with JHU-083 showed efficacy in preclinical models of IDHmut glioma and measurably decreased mTOR signaling.