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Rapid adaptation to CDK2 inhibition exposes intrinsic cell-cycle plasticity

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.

 

Comments:

The passage you provided highlights the role of CDK2, a cell-cycle kinase, in driving cell cycle progression and its hyperactivation in multiple cancers. It discusses the use of CDK2 inhibitors in preclinical models to study their effects on CDK2 substrate phosphorylation, cell-cycle progression, and drug adaptation.

One interesting finding is that while CDK1 can compensate for the loss of CDK2 in mice lacking CDK2 (Cdk2-/- mice), acute inhibition of CDK2 does not lead to CDK1 compensation. Upon CDK2 inhibition, there is a rapid loss of substrate phosphorylation, but it rebounds within several hours. This suggests that CDK4/6 activity plays a role in backstopping the inhibition of CDK2 and maintaining the proliferative program.

CDK4/6 activity sustains the hyperphosphorylation of Rb1, which is important for active E2F transcription and the expression of cyclin A2. These processes enable the re-activation of CDK2 in the presence of the CDK2 inhibitor. Essentially, CDK4/6 activity acts as a mechanism to support cell cycle progression and counteract the effects of CDK2 inhibition.

Based on these results, the passage suggests that co-inhibition of both CDK2 and CDK4/6 may be necessary to effectively suppress adaptation to CDK2 inhibitors in clinical development. This insight into the plasticity of CDK regulation provides valuable information for the development of combination therapies targeting CDKs in cancer treatment.

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Cat.No. Product Name Information
S8816 PF-06873600 PF-06873600 is an inhibitor of cyclin-dependent kinase 2 (CDK2), CDK4, and CDK6 with Ki values of 0.1, 1.2, and 0.1 nM, respectively, blocks the phosphorylation of retinoblastoma protein (RB1), and limits the proliferation of OVCAR-3 ovarian cancer cells with EC50s of 19 and 45 nM, respectively.

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CDK