Tanaka Kazuhiro, Sasayama Takashi, Irino Yasuhiro, Takata Kumi, Nagashima Hiroaki, Satoh Naoko, Kyotani Katsusuke, Mizowaki Takashi, Imahori Taichiro, Ejima Yasuo, Masui Kenta, Gini Beatrice, Yang Huijun, Hosoda Kohkichi, Sasaki Ryohei, Mischel Paul S, Kohmura Eiji
J Clin Invest. 2015 Apr;125(4):1591-602. doi: 10.1172/JCI78239. Epub 2015 Mar 23.
The mechanistic target of rapamycin (mTOR) is hyperactivated in many types of cancer, rendering it a compelling drug target; however, the impact of mTOR inhibition on metabolic reprogramming in cancer is incompletely understood. Here, by integrating metabolic and functional studies in glioblastoma multiforme (GBM) cell lines, preclinical models, and clinical samples, we demonstrate that the compensatory upregulation of glutamine metabolism promotes resistance to mTOR kinase inhibitors. Metabolomic studies in GBM cells revealed that glutaminase (GLS) and glutamate levels are elevated following mTOR kinase inhibitor treatment. Moreover, these mTOR inhibitor-dependent metabolic alterations were confirmed in a GBM xenograft model. Expression of GLS following mTOR inhibitor treatment promoted GBM survival in an α-ketoglutarate-dependent (αKG-dependent) manner. Combined genetic and/or pharmacological inhibition of mTOR kinase and GLS resulted in massive synergistic tumor cell death and growth inhibition in tumor-bearing mice. These results highlight a critical role for compensatory glutamine metabolism in promoting mTOR inhibitor resistance and suggest that rational combination therapy has the potential to suppress resistance.
雷帕霉素的作用靶点（mTOR）在多种癌症中被过度激活，使其成为一个极具吸引力的药物靶点；然而，mTOR抑制对癌症代谢重编程的影响尚未完全明确。在此，通过整合多形性胶质母细胞瘤（GBM）细胞系、临床前模型和临床样本中的代谢与功能研究，我们证明谷氨酰胺代谢的代偿性上调促进了对mTOR激酶抑制剂的耐药性。GBM细胞的代谢组学研究表明，mTOR激酶抑制剂处理后谷氨酰胺酶（GLS）和谷氨酸水平升高。此外，这些依赖于mTOR抑制剂的代谢改变在GBM异种移植模型中得到了证实。mTOR抑制剂处理后GLS的表达以α-酮戊二酸依赖性（αKG依赖性）方式促进了GBM的存活。mTOR激酶和GLS的联合基因和/或药理学抑制导致荷瘤小鼠出现大量协同性肿瘤细胞死亡和生长抑制。这些结果突出了代偿性谷氨酰胺代谢在促进mTOR抑制剂耐药性中的关键作用，并表明合理的联合治疗有可能抑制耐药性。
