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

Crozier, L. et al. (2023) CDK4/6 inhibitor-mediated cell overgrowth triggers osmotic and replication stress to promote senescence. Molecular Cell, 83(22), 4062-4077.e5. (doi: 10.1016/j.molcel.2023.10.016) (PMID:37977118)

Abstract

Summary. 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.

• Item Type: Articles
• Additional Information: This work was supported by a Cancer Research UK Programme Foundation Award to A.T.S. (C47320/A21229), which also funds L.C. and R.F.; a Tenovus Scotland Studentship (which funded R.F.); a Medical Research Council (UK) Doctoral Training Program Studentship (which funded L.C.); a Ninewells Cancer Campaign studentship (which funds A.U.P.), a Wellcome Trust Investigator Award to A.T.S. (222494/Z/21/Z), which also funds J.M.V., a Wellcome-Royal Society Sir Henry Dale Fellowship to T.L. (206211/A/17/Z, 218305/Z/19/Z), a CRUK Career Development Fellowship to A.R.B. (C63833/A25729), and MRC-LMS core funding to A.R.B. to support R.A., J.A.H., and W.A.W. (MC-A658-5TY60).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Whitfield, Mr Phil and Regnault, Mr Clement
• Authors: Crozier, L., Foy, R., Adib, R., Kar, A., Holt, J. A., Pareri, A. U., Valverde, J. M., Rivera, R., Weston, W. A., Wilson, R., Regnault, C., Whitfield, P., Badonyi, M., Bennett, L. G., Vernon, E. G., Gamble, A., Marsh, J. A., Staples, C. J., Saurin, A. T., Barr, A. R., and Ly, T.
• College/School: College of Medical Veterinary and Life Sciences
• Journal Name: Molecular Cell
• Publisher: Elsevier (Cell Press)
• ISSN: 1097-2765
• ISSN (Online): 1097-4164
• Copyright Holders: Copyright © 2023 The Author(s)
• First Published: First published in Molecular Cell 83(22):4062-4077.e5
• Publisher Policy: Reproduced under a creative commons licence