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  3. CDK4/6 inhibitor-mediated cell overgrowth triggers osmotic and replication stress to promote senescence

CDK4/6 inhibitor-mediated cell overgrowth triggers osmotic and replication stress to promote senescence

  • Mol Cell. 2023 Nov 16;83(22):4062-4077.e5. doi: 10.1016/j.molcel.2023.10.016.
Lisa Crozier 1,  Reece Foy 1,  Rozita Adib 2,  Ananya Kar 3,  Jordan A Holt 2,  Aanchal U Pareri 1,  Juan M Valverde 1,  Rene Rivera 3,  William A Weston 2,  Rona Wilson 4,  Clement Regnault 5,  Phil Whitfield 5,  Mihaly Badonyi 6,  Laura G Bennett 7,  Ellen G Vernon 7,  Amelia Gamble 7,  Joseph A Marsh 6,  Christopher J Staples 7,  Adrian T Saurin 8,  Alexis R Barr 9,  Tony Ly 10
Affiliations

Affiliations

  • 1 Cellular and Systems Medicine, Jacqui Wood Cancer Centre, School of Medicine, University of Dundee, Dundee, UK.
  • 2 MRC Laboratory of Medical Sciences, London, UK.
  • 3 Molecular Cell and Developmental Biology, School of Life Sciences, Dundee, UK.
  • 4 Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UK.
  • 5 Glasgow Polyomics College of Medical, Veterinary, and Life Sciences, University of Glasgow, UK.
  • 6 MRC Human Genetics Unit, University of Edinburgh, Edinburgh, UK.
  • 7 North West Cancer Research Institute, School of Medical and Health Sciences, Brambell Building, Deiniol Rd, Bangor LL57 2UW, UK.
  • 8 Cellular and Systems Medicine, Jacqui Wood Cancer Centre, School of Medicine, University of Dundee, Dundee, UK. Electronic address: a.saurin@dundee.ac.uk.
  • 9 MRC Laboratory of Medical Sciences, London, UK; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK. Electronic address: a.barr@lms.mrc.ac.uk.
  • 10 Molecular Cell and Developmental Biology, School of Life Sciences, Dundee, UK; Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UK; Glasgow Polyomics College of Medical, Veterinary, and Life Sciences, University of Glasgow, UK. Electronic address: t.ly@dundee.ac.uk.
PMID: 37977118 DOI: 10.1016/j.molcel.2023.10.016
Abstract

Abnormal increases in cell size are associated with senescence and cell cycle exit. The mechanisms by which overgrowth primes cells to withdraw from the cell cycle remain unknown. We address this question using CDK4/6 inhibitors, which arrest cells in G0/G1 and are licensed to treat advanced HR+/HER2- breast Cancer. We demonstrate that CDK4/6-inhibited cells overgrow during G0/G1, causing p38/p53/p21-dependent cell cycle withdrawal. Cell cycle withdrawal is triggered by biphasic p21 induction. The first p21 wave is caused by osmotic stress, leading to p38- and size-dependent accumulation of p21. CDK4/6 inhibitor washout results in some cells entering S-phase. Overgrown cells experience replication stress, resulting in a second p21 wave that promotes cell cycle withdrawal from G2 or the subsequent G1. We propose that the levels of p21 integrate signals from overgrowth-triggered stresses to determine cell fate. This model explains how hypertrophy can drive senescence and why CDK4/6 inhibitors have long-lasting effects in patients.

Keywords

DNA damage; cell cycle; cell growth; cell size; mTOR; p21(Cip1/Waf1); p38MAPK; p53; palbociclib; rapamycin.

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