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De novo MYC addiction as an adaptive response of cancer cells to CDK4/6 inhibition.
Molecular Systems Biology ( IF 9.9 ) Pub Date : 2017-10-04 , DOI: 10.15252/msb.20167321
Míriam Tarrado-Castellarnau 1, 2 , Pedro de Atauri 1, 2 , Josep Tarragó-Celada 1, 2 , Jordi Perarnau 1, 2 , Mariia Yuneva 3 , Timothy M Thomson 4 , Marta Cascante 2, 5
Affiliation  

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.

中文翻译:

从头 MYC 成瘾作为癌细胞对 CDK4/6 抑制的适应性反应。

细胞周期蛋白依赖性激酶 (CDK) 是合理的癌症治疗靶点,充满了肿瘤细胞产生的获得性耐药性。通过代谢和转录组学分析,我们表明 CDK4/6 的抑制导致与由 MYC 转录因子协调的基因网络相关的代谢重编程。在抑制 CDK4/6 后,MYC 蛋白的积累随之而来,这解释了谷氨酰胺代谢增加、mTOR 通路激活和 HIF-1α 介导的对缺氧的反应减弱。这些由 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 抑制剂和缺氧高度敏感,
更新日期:2019-11-01
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