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Oncogenic signals prime cancer cells for toxic cell growth during a G1 cell cycle arrest

View ORCID ProfileReece Foy, View ORCID ProfileLisa Crozier, Aanchal U Pareri, Ben Ho Park, View ORCID ProfileAdrian T Saurin
doi: https://doi.org/10.1101/2022.09.08.506962
Reece Foy
1Cellular and Systems Medicine, Jacqui Wood Cancer Centre, School of Medicine, University of Dundee, Dundee, UK
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Lisa Crozier
1Cellular and Systems Medicine, Jacqui Wood Cancer Centre, School of Medicine, University of Dundee, Dundee, UK
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Aanchal U Pareri
1Cellular and Systems Medicine, Jacqui Wood Cancer Centre, School of Medicine, University of Dundee, Dundee, UK
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Ben Ho Park
2Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States of America
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Adrian T Saurin
1Cellular and Systems Medicine, Jacqui Wood Cancer Centre, School of Medicine, University of Dundee, Dundee, UK
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  • For correspondence: a.saurin@dundee.ac.uk
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SUMMARY

A long-term goal in cancer research has been to inhibit the cell cycle in tumour cells without causing toxicity in proliferative healthy tissues. The best evidence that this is achievable is provided by CDK4/6 inhibitors, which arrest the cell cycle in G1, are well-tolerated in patients, and are effective in treating ER+/HER2-breast cancer. CDK4/6 inhibitors are effective because they arrest tumour cells more efficiently than some healthy cell types and, in addition, they affect the tumour microenvironment to enhance anti-tumour immunity. We demonstrate here another reason to explain their efficacy. Tumour cells are specifically vulnerable to CDK4/6 inhibition because during the G1 arrest, oncogenic signals drive toxic cell overgrowth. This overgrowth causes permanent cell cycle withdrawal by either preventing exit from G1 or by inducing replication stress and genotoxic damage during the subsequent S-phase and mitosis. Inhibiting or reverting oncogenic signals that converge onto mTOR can rescue this excessive growth, DNA damage and cell cycle exit in cancer cells. Conversely, inducing oncogenic signals in non-transformed cells can drive these toxic phenotypes and sensitize cells to CDK4/6 inhibition. Together, this demonstrates how oncogenic signals that have evolved to stimulate constitutive tumour growth and proliferation can be driven to cause toxic cell growth and irreversible cell cycle exit when proliferation is halted in G1.

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 September 08, 2022.
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Oncogenic signals prime cancer cells for toxic cell growth during a G1 cell cycle arrest
Reece Foy, Lisa Crozier, Aanchal U Pareri, Ben Ho Park, Adrian T Saurin
bioRxiv 2022.09.08.506962; doi: https://doi.org/10.1101/2022.09.08.506962
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Oncogenic signals prime cancer cells for toxic cell growth during a G1 cell cycle arrest
Reece Foy, Lisa Crozier, Aanchal U Pareri, Ben Ho Park, Adrian T Saurin
bioRxiv 2022.09.08.506962; doi: https://doi.org/10.1101/2022.09.08.506962

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