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Sensitivity to inhibition of DNA repair by Olaparib in novel oropharyngeal cancer cell lines infected with Human Papillomavirus

The incidence of Human Papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is increasing rapidly in the UK. Patients with HPV-positive OPSCC generally show superior clinical responses relative to HPV-negative patients. We hypothesised that these superior responses could be...

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Autores principales: Pirotte, Evelyne F., Holzhauser, Stefan, Owens, David, Quine, Stuart, Al-Hussaini, Ali, Christian, Adam D., Giles, Peter J., Man, Stephen T., Evans, Mererid, Powell, Ned G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292594/
https://www.ncbi.nlm.nih.gov/pubmed/30543656
http://dx.doi.org/10.1371/journal.pone.0207934
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author Pirotte, Evelyne F.
Holzhauser, Stefan
Owens, David
Quine, Stuart
Al-Hussaini, Ali
Christian, Adam D.
Giles, Peter J.
Man, Stephen T.
Evans, Mererid
Powell, Ned G.
author_facet Pirotte, Evelyne F.
Holzhauser, Stefan
Owens, David
Quine, Stuart
Al-Hussaini, Ali
Christian, Adam D.
Giles, Peter J.
Man, Stephen T.
Evans, Mererid
Powell, Ned G.
author_sort Pirotte, Evelyne F.
collection PubMed
description The incidence of Human Papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is increasing rapidly in the UK. Patients with HPV-positive OPSCC generally show superior clinical responses relative to HPV-negative patients. We hypothesised that these superior responses could be associated with defective repair of DNA double strand breaks (DSB). The study aimed to determine whether defective DNA repair could be associated with sensitivity to inhibition of DNA repair using the PARP inhibitor Olaparib. Sensitivity to Olaparib, and induction and repair of DNA damage, were assessed in a panel of 8 OPSCC cell-lines, including 2 novel HPV-positive lines. Effects on cell cycle distribution and levels of PARP1 and p53 were quantified. RNA-sequencing was used to assess differences in activity of DNA repair pathways. Two HPV-positive OPSCC lines were sensitive to Olaparib at potentially therapeutic doses (0.1–0.5 μM). Two HPV-negative lines were sensitive at an intermediate dose. Four other lines, derived from HPV-positive and HPV-negative tumours, were resistant to PARP inhibition. Only one cell-line, UPCISCC90, showed results consistent with the original hypothesis i.e. that in HPV-positive cells, treatment with Olaparib would cause accumulation of DSB, resulting in cell cycle arrest. There was no evidence that HPV-positive tumours exhibit defective repair of DSB. However, the data suggest that a subset of OPSCC may be susceptible to PARP-inhibitor based therapy.
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spelling pubmed-62925942018-12-28 Sensitivity to inhibition of DNA repair by Olaparib in novel oropharyngeal cancer cell lines infected with Human Papillomavirus Pirotte, Evelyne F. Holzhauser, Stefan Owens, David Quine, Stuart Al-Hussaini, Ali Christian, Adam D. Giles, Peter J. Man, Stephen T. Evans, Mererid Powell, Ned G. PLoS One Research Article The incidence of Human Papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is increasing rapidly in the UK. Patients with HPV-positive OPSCC generally show superior clinical responses relative to HPV-negative patients. We hypothesised that these superior responses could be associated with defective repair of DNA double strand breaks (DSB). The study aimed to determine whether defective DNA repair could be associated with sensitivity to inhibition of DNA repair using the PARP inhibitor Olaparib. Sensitivity to Olaparib, and induction and repair of DNA damage, were assessed in a panel of 8 OPSCC cell-lines, including 2 novel HPV-positive lines. Effects on cell cycle distribution and levels of PARP1 and p53 were quantified. RNA-sequencing was used to assess differences in activity of DNA repair pathways. Two HPV-positive OPSCC lines were sensitive to Olaparib at potentially therapeutic doses (0.1–0.5 μM). Two HPV-negative lines were sensitive at an intermediate dose. Four other lines, derived from HPV-positive and HPV-negative tumours, were resistant to PARP inhibition. Only one cell-line, UPCISCC90, showed results consistent with the original hypothesis i.e. that in HPV-positive cells, treatment with Olaparib would cause accumulation of DSB, resulting in cell cycle arrest. There was no evidence that HPV-positive tumours exhibit defective repair of DSB. However, the data suggest that a subset of OPSCC may be susceptible to PARP-inhibitor based therapy. Public Library of Science 2018-12-13 /pmc/articles/PMC6292594/ /pubmed/30543656 http://dx.doi.org/10.1371/journal.pone.0207934 Text en © 2018 Pirotte et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Pirotte, Evelyne F.
Holzhauser, Stefan
Owens, David
Quine, Stuart
Al-Hussaini, Ali
Christian, Adam D.
Giles, Peter J.
Man, Stephen T.
Evans, Mererid
Powell, Ned G.
Sensitivity to inhibition of DNA repair by Olaparib in novel oropharyngeal cancer cell lines infected with Human Papillomavirus
title Sensitivity to inhibition of DNA repair by Olaparib in novel oropharyngeal cancer cell lines infected with Human Papillomavirus
title_full Sensitivity to inhibition of DNA repair by Olaparib in novel oropharyngeal cancer cell lines infected with Human Papillomavirus
title_fullStr Sensitivity to inhibition of DNA repair by Olaparib in novel oropharyngeal cancer cell lines infected with Human Papillomavirus
title_full_unstemmed Sensitivity to inhibition of DNA repair by Olaparib in novel oropharyngeal cancer cell lines infected with Human Papillomavirus
title_short Sensitivity to inhibition of DNA repair by Olaparib in novel oropharyngeal cancer cell lines infected with Human Papillomavirus
title_sort sensitivity to inhibition of dna repair by olaparib in novel oropharyngeal cancer cell lines infected with human papillomavirus
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292594/
https://www.ncbi.nlm.nih.gov/pubmed/30543656
http://dx.doi.org/10.1371/journal.pone.0207934
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