Next Article in Journal
Sperm Protein 17 Expression by Murine Epithelial Ovarian Cancer Cells and Its Impact on Tumor Progression
Next Article in Special Issue
High-Dose-Rate Brachytherapy Monotherapy versus Image-Guided Intensity-Modulated Radiotherapy with Helical Tomotherapy for Patients with Localized Prostate Cancer
Previous Article in Journal
Genetics and Expression Profile of the Tubulin Gene Superfamily in Breast Cancer Subtypes and Its Relation to Taxane Resistance
Article Menu
Issue 8 (August) cover image

Export Article

Open AccessFeature PaperArticle
Cancers 2018, 10(8), 275;

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

Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
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)
Full-Text   |   PDF [1432 KB, uploaded 21 August 2018]   |  


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

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

Supplementary material


Share & Cite This Article

MDPI and ACS Style

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.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics



[Return to top]
Cancers EISSN 2072-6694 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top