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The impact of p53 dysfunction in ATR inhibitor cytotoxicity and chemo-and radiosensitisation

Lookup NU author(s): Fiona Middleton, Professor Nicola Curtin

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2018 by the authors. Licensee MDPI, Basel, Switzerland. Ataxia telangiectasia mutated and Rad3 related kinase (ATR) signals replication stress and DNA damage to S and G2 arrest and promotes DNA repair. Mutations in p53, critical for G1 checkpoint control, are common in cancer and predicted to confer vulnerability to ATR inhibitors. Reported data on the impact of p53 status are variable possibly because of the use of unmatched cells and surrogate endpoints of survival. The cytotoxicity of VE-821 alone and its ability to potentiate radiation and gemcitabine cytotoxicity was determined in isogenic and unmatched p53 wild-type (wt) and null/mutant cells, as well as immortalised nonmalignant MCF10 (immortalised non-neoplastic) cells, by colony-forming assay. The effect on cell cycle checkpoints was determined by flow cytometry. The isogenic p53 defective cells were not more sensitive to VE-821 alone. Defective p53 consistently conferred greater chemo-and radiosensitisation, particularly at high dose levels in isogenic cells but not unmatched cells. VE-821 did not sensitise MCF10 cells. We conclude that p53 status is just one factor contributing to chemo-and radiosensitisation by ATR inhibition, the lack of chemo-or radiosensitisation in the noncancerous cells suggests an element of tumour-specificity that warrants further investigation. The greater sensitisation at high-dose irradiation suggests that ATR inhibitors may be most effective with hypofractionated radiotherapy.


Publication metadata

Author(s): Middleton FK, Pollard JR, Curtin NJ

Publication type: Article

Publication status: Published

Journal: Cancers

Year: 2018

Volume: 10

Issue: 8

Online publication date: 20/08/2018

Acceptance date: 14/08/2018

Date deposited: 26/09/2018

ISSN (electronic): 2072-6694

Publisher: MDPI AG

URL: https://doi.org/10.3390/cancers10080275

DOI: 10.3390/cancers10080275


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