Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain.
Institute of Biomedicine of Universitat de Barcelona (IBUB) and CSIC-Associated Unit, Barcelona, Spain.
Mol Syst Biol. 2017 Oct 4;13(10):940. doi: 10.15252/msb.20167321.
Cyclin-dependent kinases (CDK) are rational cancer therapeutic targets fraught with the development of acquired resistance by tumor cells. Through metabolic and transcriptomic analyses, we show that the inhibition of CDK4/6 leads to a metabolic reprogramming associated with gene networks orchestrated by the MYC transcription factor. Upon inhibition of CDK4/6, an accumulation of MYC protein ensues which explains an increased glutamine metabolism, activation of the mTOR pathway and blunting of HIF-1α-mediated responses to hypoxia. These MYC-driven adaptations to CDK4/6 inhibition render cancer cells highly sensitive to inhibitors of MYC, glutaminase or mTOR and to hypoxia, demonstrating that metabolic adaptations to antiproliferative drugs unveil new vulnerabilities that can be exploited to overcome acquired drug tolerance and resistance by cancer cells.
细胞周期蛋白依赖性激酶（CDK）是癌症治疗的合理靶点，但肿瘤细胞容易产生获得性耐药。通过代谢组学和转录组学分析，我们发现 CDK4/6 的抑制会导致与 MYC 转录因子协调的基因网络相关的代谢重编程。在 CDK4/6 被抑制后，MYC 蛋白积累，导致谷氨酰胺代谢增加，mTOR 途径激活，以及 HIF-1α 介导的对缺氧反应减弱。这些 MYC 驱动的对 CDK4/6 抑制的适应使癌细胞对 MYC、谷氨酰胺酶或 mTOR 的抑制剂以及缺氧高度敏感，表明代谢对抗增殖药物的适应揭示了新的弱点，可用于克服癌细胞获得性药物耐受和耐药性。
