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Cancers 2018, 10(8), 275; https://doi.org/10.3390/cancers10080275

The Impact of p53 Dysfunction in ATR Inhibitor Cytotoxicity and Chemo- and Radiosensitisation

1
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
2
Vertex Pharmaceuticals (Europe) Limited, Milton Park, Abingdon, Oxfordshire OX14 4RY, UK
Now at Commercial Partnerships team Cancer Research UK, Angel Building, 407 St John Street, London EC1V 4AD, UK.
*
Author to whom correspondence should be addressed.
Received: 2 July 2018 / Revised: 27 July 2018 / Accepted: 14 August 2018 / Published: 20 August 2018
(This article belongs to the Special Issue New Developments in Radiotherapy)
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Abstract

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. View Full-Text
Keywords: ATR; p53; radiation; gemcitabine; cytotoxicity; cell cycle ATR; p53; radiation; gemcitabine; cytotoxicity; cell cycle
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Middleton, F.K.; Pollard, J.R.; Curtin, N.J. The Impact of p53 Dysfunction in ATR Inhibitor Cytotoxicity and Chemo- and Radiosensitisation. Cancers 2018, 10, 275.

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