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.

CDK2 是一种核心细胞周期激酶，可磷酸化许多底物以驱动细胞周期的进展。CDK2 在多种癌症中过度激活，因此是一个有吸引力的治疗靶点。在这里，我们在临床开发中使用几种 CDK2 抑制剂来研究临床前模型中的 CDK2 底物磷酸化、细胞周期进展和药物适应。虽然已知 CDK1 可以补偿Cdk2 ^−/−小鼠中 CDK2 的损失，但 CDK2 的急性抑制却并非如此。抑制 CDK2 后，细胞表现出底物磷酸化的快速丧失，并在数小时内反弹。CDK4/6 活性可阻止 CDK2 的抑制，并通过维持 Rb1 过度磷酸化、活跃的 E2F 转录和细胞周期蛋白 A2 表达来维持增殖程序，从而在药物存在下重新激活 CDK2。我们的结果增强了我们对 CDK 可塑性的理解，并表明可能需要同时抑制 CDK2 和 CDK4/6 来抑制对目前正在临床评估的 CDK2 抑制剂的适应。