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Effect of ATR Inhibition in RT Response of HPV-Negative and HPV-Positive Head and Neck Cancers

Radiotherapy (RT) has a central role in head and neck squamous cell carcinoma (HNSCC) treatment. Targeted therapies modulating DNA damage response (DDR) and more specific cell cycle checkpoints can improve the radiotherapeutic response. Here, we assessed the influence of ataxia-telangiectasia mutate...

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Autores principales: Dok, Rüveyda, Glorieux, Mary, Bamps, Marieke, Nuyts, Sandra
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913134/
https://www.ncbi.nlm.nih.gov/pubmed/33546122
http://dx.doi.org/10.3390/ijms22041504
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author Dok, Rüveyda
Glorieux, Mary
Bamps, Marieke
Nuyts, Sandra
author_facet Dok, Rüveyda
Glorieux, Mary
Bamps, Marieke
Nuyts, Sandra
author_sort Dok, Rüveyda
collection PubMed
description Radiotherapy (RT) has a central role in head and neck squamous cell carcinoma (HNSCC) treatment. Targeted therapies modulating DNA damage response (DDR) and more specific cell cycle checkpoints can improve the radiotherapeutic response. Here, we assessed the influence of ataxia-telangiectasia mutated and Rad3-related (ATR) inhibition with the ATR inhibitor AZD6738 on RT response in both human papillomavirus (HPV)-negative and HPV-positive HNSCC. We found that ATR inhibition enhanced RT response in HPV-negative and HPV-positive cell lines independent of HPV status. The radiosensitizing effect of AZD6738 was correlated with checkpoint kinase 1 (CHK1)-mediated abrogation of G2/M-arrest. This resulted in the inhibition of RT-induced DNA repair and in an increase in the percentage of micronucleated cells. We validated the enhanced RT response in HPV-negative and HPV-positive xenograft models. These data demonstrate the potential use of ATR inhibition in combination with RT as a treatment option for both HPV-negative and HPV-positive HNSCC patients.
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spelling pubmed-79131342021-02-28 Effect of ATR Inhibition in RT Response of HPV-Negative and HPV-Positive Head and Neck Cancers Dok, Rüveyda Glorieux, Mary Bamps, Marieke Nuyts, Sandra Int J Mol Sci Article Radiotherapy (RT) has a central role in head and neck squamous cell carcinoma (HNSCC) treatment. Targeted therapies modulating DNA damage response (DDR) and more specific cell cycle checkpoints can improve the radiotherapeutic response. Here, we assessed the influence of ataxia-telangiectasia mutated and Rad3-related (ATR) inhibition with the ATR inhibitor AZD6738 on RT response in both human papillomavirus (HPV)-negative and HPV-positive HNSCC. We found that ATR inhibition enhanced RT response in HPV-negative and HPV-positive cell lines independent of HPV status. The radiosensitizing effect of AZD6738 was correlated with checkpoint kinase 1 (CHK1)-mediated abrogation of G2/M-arrest. This resulted in the inhibition of RT-induced DNA repair and in an increase in the percentage of micronucleated cells. We validated the enhanced RT response in HPV-negative and HPV-positive xenograft models. These data demonstrate the potential use of ATR inhibition in combination with RT as a treatment option for both HPV-negative and HPV-positive HNSCC patients. MDPI 2021-02-03 /pmc/articles/PMC7913134/ /pubmed/33546122 http://dx.doi.org/10.3390/ijms22041504 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Dok, Rüveyda
Glorieux, Mary
Bamps, Marieke
Nuyts, Sandra
Effect of ATR Inhibition in RT Response of HPV-Negative and HPV-Positive Head and Neck Cancers
title Effect of ATR Inhibition in RT Response of HPV-Negative and HPV-Positive Head and Neck Cancers
title_full Effect of ATR Inhibition in RT Response of HPV-Negative and HPV-Positive Head and Neck Cancers
title_fullStr Effect of ATR Inhibition in RT Response of HPV-Negative and HPV-Positive Head and Neck Cancers
title_full_unstemmed Effect of ATR Inhibition in RT Response of HPV-Negative and HPV-Positive Head and Neck Cancers
title_short Effect of ATR Inhibition in RT Response of HPV-Negative and HPV-Positive Head and Neck Cancers
title_sort effect of atr inhibition in rt response of hpv-negative and hpv-positive head and neck cancers
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913134/
https://www.ncbi.nlm.nih.gov/pubmed/33546122
http://dx.doi.org/10.3390/ijms22041504
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