Published on Thu Feb 04 2021

CDK4/6 inhibitors induce replication stress to cause long-term cell cycle withdrawal

Crozier, L., Foy, R., Mouery, B. L., Whitaker, R. H., Corno, A., Spanos, C., Ly, T., Cook, J. G., Saurin, A. T.

CDK4/6 inhibitors arrest the cell cycle in G1-phase. This causes a failure in DNA replication after release from that arrest. If p53 is absent, then cells bypass the G2-checkpoint.

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Abstract

AO_SCPLOWBSTRACTC_SCPLOWCDK4/6 inhibitors arrest the cell cycle in G1-phase. They are approved to treat breast cancer and are also undergoing clinical trials against a range of other tumour types. To facilitate these efforts, it is important to understand why a cytostatic arrest in G1 causes long-lasting effects on tumour growth. Here we demonstrate that a prolonged G1-arrest following CDK4/6 inhibition downregulates replisome components and impairs origin licencing. This causes a failure in DNA replication after release from that arrest, resulting in a p53-dependent withdrawal from the cell cycle. If p53 is absent, then cells bypass the G2-checkpoint and undergo a catastrophic mitosis resulting in excessive DNA damage. These data therefore link CDK4/6 inhibition to genotoxic stress; a phenotype that is shared by most other broad-spectrum anti-cancer drugs. This provides a rationale to predict responsive tumour types and effective combination therapies, as demonstrated by the fact that CDK4/6 inhibition induces sensitivity to chemotherapeutics that also cause replication stress.