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

Lisa Crozier, Reece Foy, View ORCID ProfileBrandon L. Mouery, View ORCID ProfileRobert H. Whitaker, View ORCID ProfileAndrea Corno, View ORCID ProfileChristos Spanos, View ORCID ProfileTony Ly, View ORCID ProfileJeanette Gowen Cook, View ORCID ProfileAdrian T. Saurin
doi: https://doi.org/10.1101/2021.02.03.428245
Lisa Crozier
1Division of Cellular Medicine, School of Medicine, University of Dundee, UK. DD1 9SY
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Reece Foy
1Division of Cellular Medicine, School of Medicine, University of Dundee, UK. DD1 9SY
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Brandon L. Mouery
2Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, University of Edinburgh, Edinburgh EH9 3BF, UK
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Robert H. Whitaker
3Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, University of Edinburgh, Edinburgh EH9 3BF, UK
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Andrea Corno
1Division of Cellular Medicine, School of Medicine, University of Dundee, UK. DD1 9SY
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Christos Spanos
4Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3BF, UK
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Tony Ly
4Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3BF, UK
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Jeanette Gowen Cook
3Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, University of Edinburgh, Edinburgh EH9 3BF, UK
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Adrian T. Saurin
1Division of Cellular Medicine, School of Medicine, University of Dundee, UK. DD1 9SY
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  • For correspondence: a.saurin@dundee.ac.uk
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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. 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.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 04, 2021.
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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 T. Saurin
bioRxiv 2021.02.03.428245; doi: https://doi.org/10.1101/2021.02.03.428245
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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 T. Saurin
bioRxiv 2021.02.03.428245; doi: https://doi.org/10.1101/2021.02.03.428245

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