生物
细胞周期
有丝分裂
细胞周期检查点
癌症研究
DNA损伤
细胞生物学
癌细胞
细胞生长
癌症
细胞
G1期
衰老
遗传学
DNA
作者
Reece Foy,Lisa Crozier,Aanchal Udaynath Pareri,Juan Manuel Valverde,Ben Ho Park,Tony Ly,Adrian T. Saurin
出处
期刊:Molecular Cell
[Elsevier]
日期:2023-11-01
卷期号:83 (22): 4047-4061.e6
被引量:19
标识
DOI:10.1016/j.molcel.2023.10.020
摘要
Summary
CDK4/6 inhibitors are remarkable anti-cancer drugs that can arrest tumor cells in G1 and induce their senescence while causing only relatively mild toxicities in healthy tissues. How they achieve this mechanistically is unclear. We show here that tumor cells are specifically vulnerable to CDK4/6 inhibition because during the G1 arrest, oncogenic signals drive toxic cell overgrowth. This overgrowth causes permanent cell cycle withdrawal by either preventing progression from G1 or inducing genotoxic damage during the subsequent S-phase and mitosis. Inhibiting or reverting oncogenic signals that converge onto mTOR can rescue this excessive growth, DNA damage, and cell cycle exit in cancer cells. Conversely, inducing oncogenic signals in non-transformed cells can drive these toxic phenotypes and sensitize the cells to CDK4/6 inhibition. Together, this demonstrates that cell cycle arrest and oncogenic cell growth is a synthetic lethal combination that is exploited by CDK4/6 inhibitors to induce tumor-specific toxicity.
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