细胞周期蛋白依赖激酶2
细胞周期蛋白依赖激酶
生物
细胞周期蛋白依赖激酶1
细胞生物学
细胞周期
癌症研究
激酶
细胞
生物化学
蛋白激酶A
作者
Mansi Arora,Justin Moser,Timothy E. Hoffman,Lotte P. Watts,Mingwei Min,Mónica Musteanu,Rong Ye,C. Ryland Ill,Varuna Nangia,Jordan Schneider,Manuel Sanclemente,John D. Lapek,Lisa Nguyen,Sherry Niessen,Stephen Dann,Todd VanArsdale,Mariano Barbacid,Nichol L.G. Miller,Steven J. Spencer
出处
期刊:Cell
[Elsevier]
日期:2023-06-01
卷期号:186 (12): 2628-2643.e21
被引量:22
标识
DOI:10.1016/j.cell.2023.05.013
摘要
CDK2 is a core cell-cycle kinase that phosphorylates many substrates to drive progression through the cell cycle. CDK2 is hyperactivated in multiple cancers and is therefore an attractive therapeutic target. Here, we use several CDK2 inhibitors in clinical development to interrogate CDK2 substrate phosphorylation, cell-cycle progression, and drug adaptation in preclinical models. Whereas CDK1 is known to compensate for loss of CDK2 in Cdk2-/- mice, this is not true of acute inhibition of CDK2. Upon CDK2 inhibition, cells exhibit a rapid loss of substrate phosphorylation that rebounds within several hours. CDK4/6 activity backstops inhibition of CDK2 and sustains the proliferative program by maintaining Rb1 hyperphosphorylation, active E2F transcription, and cyclin A2 expression, enabling re-activation of CDK2 in the presence of drug. Our results augment our understanding of CDK plasticity and indicate that co-inhibition of CDK2 and CDK4/6 may be required to suppress adaptation to CDK2 inhibitors currently under clinical assessment.
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