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

Lisa Crozier, Reece Foy, Brandon L. Mouery, Robert H. Whitaker, Andrea Corno, Christos Spanos, Tony Ly, Jeanette Gowen Cook, Adrian Saurin (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)
112 Downloads (Pure)

Abstract

CDK4/6 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. Upon release from that arrest, many cells fail to complete DNA replication and exit the cell cycle in a p53-dependent manner. If cells fail to withdraw from the cell cycle following DNA replication problems, they enter mitosis and missegregate chromosomes causing excessive DNA damage, which further limits their proliferative potential. These effects are observed in a range of tumour types, including breast cancer, implying that genotoxic stress is a common outcome of CDK4/6 inhibition. This unanticipated ability of CDK4/6 inhibitors to induce DNA damage now provides a rationale to better 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.
Original languageEnglish
Article numbere108599
Number of pages20
JournalEMBO Journal
Volume41
Issue number6
Early online date17 Jan 2022
DOIs
Publication statusPublished - 15 Mar 2022

Keywords

  • CDK6
  • cyclin-dependent kinase
  • Palbociclib
  • replication stress
  • senescence

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