Functional Determinants of Cell Cycle Plasticity and Sensitivity to CDK4/6 Inhibition.

ABSTRACT: Intrinsic or acquired resistance to clinically approved CDK4/6 inhibitors has emerged as a major obstacle that hinders their utility beyond ER⁺ breast cancer. In this study, CDK4/6-dependent and -resistant models were employed to identify functional determinants of response to pharmacologic CDK4/6 inhibitors. In all models tested, the activation of RB and inhibition of CDK2 activity emerged as determinants of sensitivity. While depleting CDK4 and 6 was sufficient to limit proliferation in specific resistance settings, RB loss rendered cells completely independent of these kinases. The main downstream target in this context was the activation status of CDK2, which was suppressed with CDK4/6 inhibition in an RB-dependent fashion. Protein levels of p27 were associated with plastici

SUBMITTER: Kumarasamy V 

PROVIDER: S-EPMC8026500 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature