Our study finds that despite the robust inhibition of CDK4/6 substrates and E2F1 effector proteins by single-agent CDK4i/6i, most tumor cells remain viable following treatment with non-physiologically high concentrations of CDK4i/6i that results in a temporary cytostatic response in vitro and in vivo followed by reactivation of the cell cycle. Here, CDK4 is linked to neoplasm.