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

Lisa Crozier; Reece Foy; Rozita Adib; Ananya Kar; Jordan A. Holt; Aanchal U. Pareri; Juan M. Valverde; Rene Rivera; William A. Weston; Rona Wilson; Clément Regnault; Phil Whitfield; Mihaly Badonyi; Laura G. Bennett; Ellen G. Vernon; Amelia Gamble; Joseph A. Marsh; Christopher J.  Staples; Adrian T Saurin; Alexis R. Barr; Tony Ly

doi:10.1016/j.molcel.2023.10.016

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

Lisa Crozier, Reece Foy, Rozita Adib, Ananya Kar, Jordan A. Holt, Aanchal U. Pareri, Juan M. Valverde, Rene Rivera, William A. Weston, Rona Wilson, Clément Regnault, Phil Whitfield, Mihaly Badonyi, Laura G. Bennett, Ellen G. Vernon, Amelia Gamble, Joseph A. Marsh, Christopher J. Staples, Adrian T Saurin, Alexis R. BarrTony Ly (Lead / Corresponding author)

Molecular Cell and Developmental Biology

Research output: Contribution to journal › Article › peer-review

15 Citations (Scopus)

49 Downloads (Pure)

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.

Original language	English
Pages (from-to)	4062-4077.e5
Number of pages	21
Journal	Molecular Cell
Volume	83
Issue number	22
DOIs	https://doi.org/10.1016/j.molcel.2023.10.016
Publication status	Published - 16 Nov 2023

Keywords

DNA damage
cell cycle
cell growth
cell size
mTOR
p21
p38MAPK
p53
palbociclib
rapamycin

ASJC Scopus subject areas

Molecular Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.molcel.2023.10.016Licence: CC BY

Final Published VersionFinal published version, 12.1 MBLicence: CC BY

Cite this

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., ... Ly, T. (2023). CDK4/6 inhibitor-mediated cell overgrowth triggers osmotic and replication stress to promote senescence. Molecular Cell, 83(22), 4062-4077.e5. https://doi.org/10.1016/j.molcel.2023.10.016

@article{e6e2226e54ec4c809d0c243867b81322,

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

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, p38MAPK, p53, palbociclib, rapamycin",

author = "Lisa Crozier and Reece Foy and Rozita Adib and Ananya Kar and Holt, {Jordan A.} and Pareri, {Aanchal U.} and Valverde, {Juan M.} and Rene Rivera and Weston, {William A.} and Rona Wilson and Cl{\'e}ment Regnault and Phil Whitfield and Mihaly Badonyi and Bennett, {Laura G.} and Vernon, {Ellen G.} and Amelia Gamble and Marsh, {Joseph A.} and Staples, {Christopher J.} and Saurin, {Adrian T} and Barr, {Alexis R.} and Tony Ly",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = nov,

day = "16",

doi = "10.1016/j.molcel.2023.10.016",

language = "English",

volume = "83",

pages = "4062--4077.e5",

journal = "Molecular Cell",

issn = "1097-2765",

publisher = "Elsevier",

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Crozier, L, Foy, R, Adib, R, Kar, A, Holt, JA, Pareri, AU , Valverde, JM , Rivera, R, Weston, WA, Wilson, R, Regnault, C, Whitfield, P, Badonyi, M, Bennett, LG, Vernon, EG, Gamble, A, Marsh, JA, Staples, CJ, Saurin, AT, Barr, AR & Ly, T 2023, 'CDK4/6 inhibitor-mediated cell overgrowth triggers osmotic and replication stress to promote senescence', Molecular Cell, vol. 83, no. 22, pp. 4062-4077.e5. https://doi.org/10.1016/j.molcel.2023.10.016

TY - JOUR

T1 - CDK4/6 inhibitor-mediated cell overgrowth triggers osmotic and replication stress to promote senescence

AU - Crozier, Lisa

AU - Foy, Reece

AU - Adib, Rozita

AU - Kar, Ananya

AU - Holt, Jordan A.

AU - Pareri, Aanchal U.

AU - Valverde, Juan M.

AU - Rivera, Rene

AU - Weston, William A.

AU - Wilson, Rona

AU - Regnault, Clément

AU - Whitfield, Phil

AU - Badonyi, Mihaly

AU - Bennett, Laura G.

AU - Vernon, Ellen G.

AU - Gamble, Amelia

AU - Marsh, Joseph A.

AU - Staples, Christopher J.

AU - Saurin, Adrian T

AU - Barr, Alexis R.

AU - Ly, Tony

PY - 2023/11/16

Y1 - 2023/11/16

N2 - 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.

AB - 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.

KW - DNA damage

KW - cell cycle

KW - cell growth

KW - cell size

KW - mTOR

KW - p21

KW - p38MAPK

KW - p53

KW - palbociclib

KW - rapamycin

UR - http://www.scopus.com/inward/record.url?scp=85176463947&partnerID=8YFLogxK

U2 - 10.1016/j.molcel.2023.10.016

DO - 10.1016/j.molcel.2023.10.016

M3 - Article

C2 - 37977118

SN - 1097-2765

VL - 83

SP - 4062-4077.e5

JO - Molecular Cell

JF - Molecular Cell

IS - 22

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Protein Phosphorylation Dynamics: Investigating A New Dimension Of Regulatory Control

Kinase-Phosphatase Coupling at the Kinetochore and the Maintenance of Chromosomal Stability (joint with University of Edinburgh)

Understanding the Proliferation-Quiescence Switch Using Quantitative Cellular Biochemistry (Sir Henry Dale Fellowship) (Transfer from University of Edinburgh)

Cite this

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Projects

Protein Phosphorylation Dynamics: Investigating A New Dimension Of Regulatory Control

Kinase-Phosphatase Coupling at the Kinetochore and the Maintenance of Chromosomal Stability (joint with University of Edinburgh)

Understanding the Proliferation-Quiescence Switch Using Quantitative Cellular Biochemistry (Sir Henry Dale Fellowship) (Transfer from University of Edinburgh)

Cite this