CDK/cyclin dependencies define extreme cancer cell-cycle heterogeneity and collateral vulnerabilities.

ABSTRACT: Progression through G1/S phase of the cell cycle is coordinated by cyclin-dependent kinase (CDK) activities. Here, we find that the requirement for different CDK activities and cyclins in driving cancer cell cycles is highly heterogeneous. The differential gene requirements associate with tumor origin and genetic alterations. We define multiple mechanisms for G1/S progression in RB-proficient models, which are CDK4/6 independent and elicit resistance to FDA-approved inhibitors. Conversely, RB-deficient models are intrinsically CDK4/6 independent, but exhibit differential requirements for cyclin E. These dependencies for CDK and cyclins associate with gene expression programs that denote intrinsically different cell-cycle states. Mining therapeutic sensitivities shows that there are recipro

SUBMITTER: Knudsen ES 

PROVIDER: S-EPMC9022184 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature