Rapid adaptation to CDK2 inhibition exposes intrinsic cell-cycle plasticity

CDK2 is really a core cell-cycle kinase that phosphorylates many substrates they are driving progression with the cell cycle. CDK2 is hyperactivated in multiple cancers and it is therefore a beautiful 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 may make amends for lack of CDK2 in Cdk2-/- rodents, this isn’t the case with acute inhibition of CDK2. Upon CDK2 inhibition, cells exhibit an immediate lack of substrate phosphorylation that rebounds within several hrs. CDK4/6 activity backstops inhibition of CDK2 and sustains the proliferative program by preserve Rb1 hyperphosphorylation, active E2F transcription, and cyclin A2 expression, enabling re-activation of CDK2 in the existence of drug. Our results augment our knowledge of CDK plasticity and indicate that co-inhibition of CDK2 and CDK4/6 might be needed to PF-06873600 suppress adaptation to CDK2 inhibitors presently under clinical assessment.