{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:45:02Z","timestamp":1790790302423,"version":"4.1.0"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,8,16]],"date-time":"2022-08-16T00:00:00Z","timestamp":1660608000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000357","name":"North West Cancer Research","doi-asserted-by":"publisher","award":["CR1197"],"award-info":[{"award-number":["CR1197"]}],"id":[{"id":"10.13039\/501100000357","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>A critical risk factor for head and neck squamous cell carcinoma (HNSCC), particularly of the oropharynx, and the response to radiotherapy is human papillomavirus (HPV) type-16\/18 infection. Specifically, HPV-positive HNSCC display increased radiosensitivity and improved outcomes, which has been linked with defective signalling and repair of DNA double-strand breaks (DSBs). This differential response to radiotherapy has been recapitulated <jats:italic>in vitro<\/jats:italic> using cell lines, although studies utilising appropriate 3D models that are more reflective of the original tumour are scarce. Furthermore, strategies to enhance the sensitivity of relatively radioresistant HPV-negative HNSCC to radiotherapy are still required. We have analysed the comparative response of <jats:italic>in vitro<\/jats:italic> 3D spheroid models of oropharyngeal squamous cell carcinoma to x-ray (photon) irradiation and provide further evidence that HPV-positive cells, in this case now grown as spheroids, show greater inherent radiosensitivity compared to HPV-negative spheroids due to defective DSB repair. We subsequently analysed these and an expanded number of spheroid models, with a particular focus on relatively radioresistant HPV-negative HNSCC, for impact of poly(ADP-ribose) polymerase (PARP) inhibitors (olaparib and talazoparib) in significantly inhibiting spheroid growth in response to photons but also proton beam therapy. We demonstrate that in general, PARP inhibition can further radiosensitise particularly HPV-negative HNSCC spheroids to photons and protons leading to significant growth suppression. The degree of enhanced radiosensitivity was observed to be dependent on the model and on the tumour site (oropharynx, larynx, salivary gland, or hypopharynx) from which the cells were derived. We also provide evidence suggesting that PARP inhibitor effectiveness relates to homologous recombination repair proficiency. Interestingly though, we observed significantly enhanced effectiveness of talazoparib versus olaparib specifically in response to proton irradiation. Nevertheless, our data generally support that PARP inhibition in combination with radiotherapy (photons and protons) should be considered further as an effective treatment for HNSCC, particularly for relatively radioresistant HPV-negative tumours.<\/jats:p>","DOI":"10.3389\/fonc.2022.940377","type":"journal-article","created":{"date-parts":[[2022,8,16]],"date-time":"2022-08-16T04:56:25Z","timestamp":1660625785000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":20,"title":["Effectiveness of PARP inhibition in enhancing the radiosensitivity of 3D spheroids of head and neck squamous cell carcinoma"],"prefix":"10.3389","volume":"12","author":[{"given":"Chumin","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Rita","family":"Fabbrizi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan R.","family":"Hughes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabrielle J.","family":"Grundy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason L.","family":"Parsons","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,8,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2013.50.3870","article-title":"Worldwide trends in incidence rates for oral cavity and oropharyngeal cancers","volume":"31","author":"Chaturvedi","year":"2013","journal-title":"J Clin Oncol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(10)70017-6","article-title":"HPV-associated head and neck cancer: A virus-related cancer epidemic","volume":"11","author":"Marur","year":"2010","journal-title":"Lancet Oncol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"75","DOI":"10.3390\/cancers8080075","article-title":"HPV associated head and neck cancer","volume":"8","author":"Spence","year":"2016","journal-title":"Cancers (Basel)"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-13-0587","article-title":"Enhanced radiation sensitivity in HPV-positive head and neck cancer","volume":"73","author":"Kimple","year":"2013","journal-title":"Cancer Res"},{"key":"B6","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1056\/NEJMoa0912217","article-title":"Human papillomavirus and survival of patients with oropharyngeal cancer","volume":"363","author":"Ang","year":"2010","journal-title":"N Engl J Med"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djn011","article-title":"Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial","volume":"100","author":"Fakhry","year":"2008","journal-title":"J Natl Cancer Inst"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2008.20.2853","article-title":"Effect of HPV-associated p16INK4A expression on response to radiotherapy and survival in squamous cell carcinoma of the head and neck","volume":"27","author":"Lassen","year":"2009","journal-title":"J Clin Oncol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.16265","article-title":"Misregulation of DNA damage repair pathways in HPV-positive head and neck squamous cell carcinoma contributes to cellular radiosensitivity","volume":"8","author":"Nickson","year":"2017","journal-title":"Oncotarget"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.4863","article-title":"DNA Double strand break repair defect and sensitivity to poly ADP-ribose polymerase (PARP) inhibition in human papillomavirus 16-positive head and neck squamous cell carcinoma","volume":"6","author":"Weaver","year":"2015","journal-title":"Oncotarget"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.radonc.2013.03.013","article-title":"HNSCC cell lines positive for HPV and p16 possess higher cellular radiosensitivity due to an impaired DSB repair capacity","volume":"107","author":"Rieckmann","year":"2013","journal-title":"Radiother Oncol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-11-2058","article-title":"Downregulation of SMG-1 in HPV-positive head and neck squamous cell carcinoma due to promoter hypermethylation correlates with improved survival","volume":"18","author":"Gubanova","year":"2012","journal-title":"Clin Cancer Res"},{"key":"B13","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.dnarep.2016.02.003","article-title":"Reduced DNA double-strand break repair capacity and risk of squamous cell carcinoma of the head and neck\u2013a case-control study","volume":"40","author":"Liu","year":"2016","journal-title":"DNA Repair (Amst)"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1963","article-title":"Poly(ADP-ribose): novel functions for an old molecule","volume":"7","author":"Schreiber","year":"2006","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1042\/EBC20200013","article-title":"Base excision repair and its implications to cancer therapy","volume":"64","author":"Grundy","year":"2020","journal-title":"Ess Biochem"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/nature03445","article-title":"Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy","volume":"434","author":"Farmer","year":"2005","journal-title":"Nature"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/nature03443","article-title":"Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase","volume":"434","author":"Bryant","year":"2005","journal-title":"Nature"},{"key":"B18","doi-asserted-by":"publisher","first-page":"e2","DOI":"10.1017\/erm.2021.31","article-title":"Cell death mechanisms in head and neck cancer cells in response to low and high-LET radiation","volume":"24","author":"Fabbrizi","year":"2022","journal-title":"Expert Rev Mol Med"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-2753","article-title":"Trapping of PARP1 and PARP2 by clinical PARP inhibitors","volume":"72","author":"Murai","year":"2012","journal-title":"Cancer Res"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdz192","article-title":"A decade of clinical development of PARP inhibitors in perspective","volume":"30","author":"Mateo","year":"2019","journal-title":"Ann Oncol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-13-0803","article-title":"Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib","volume":"13","author":"Murai","year":"2014","journal-title":"Mol Cancer Ther"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-15-0191-T","article-title":"Mechanistic dissection of PARP1 trapping and the impact on In vivo tolerability and efficacy of PARP inhibitors","volume":"13","author":"Hopkins","year":"2015","journal-title":"Mol Cancer Res"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2017.11.012","article-title":"Complex DNA damage induced by high linear energy transfer alpha-particles and protons triggers a specific cellular DNA damage response","volume":"100","author":"Carter","year":"2018","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2019.02.053","article-title":"Characterisation of deubiquitylating enzymes in the cellular response to high-LET ionizing radiation and complex DNA damage","volume":"104","author":"Carter","year":"2019","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1097\/CCO.0000000000000181","article-title":"Proton therapy for head and neck cancer","volume":"27","author":"Lukens","year":"2015","journal-title":"Curr Opin Oncol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(17)30179-1","article-title":"Proton therapy for head and neck cancer: Expanding the therapeutic window","volume":"18","author":"Leeman","year":"2017","journal-title":"Lancet Oncol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.32558","article-title":"Radiosensitization approaches for HPV-positive and HPV-negative head and neck squamous carcinomas","volume":"146","author":"Dok","year":"2020","journal-title":"Int J Cancer"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.6947","article-title":"PARP1 inhibition radiosensitizes HNSCC cells deficient in homologous recombination by disabling the DNA replication fork elongation response","volume":"7","author":"Wurster","year":"2016","journal-title":"Oncotarget"},{"key":"B29","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1158\/1541-7786.MCR-16-0157","article-title":"AXL inhibition suppresses the DNA damage response and sensitizes cells to PARP inhibition in multiple cancers","volume":"15","author":"Balaji","year":"2017","journal-title":"Mol Cancer Res"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-19-0514","article-title":"PARP inhibition enhances radiotherapy of SMAD4-deficient human head and neck squamous cell carcinomas in experimental models","volume":"26","author":"Hernandez","year":"2020","journal-title":"Clin Cancer Res"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3390\/cancers11070946","article-title":"The radiobiological effects of proton beam therapy: Impact on DNA damage and repair","volume":"11","author":"Vitti","year":"2019","journal-title":"Cancers (Basel)"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12061490","article-title":"Targeting DNA double-strand break repair enhances radiosensitivity of HPV-positive and HPV-negative head and neck squamous cell carcinoma to photons and protons","volume":"12","author":"Vitti","year":"2020","journal-title":"Cancers (Basel)"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2015.01.034","article-title":"Biology of Poly(ADP-ribose) polymerases: The factotums of cell maintenance","volume":"58","author":"Bai","year":"2015","journal-title":"Mol Cell"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2022.940377\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,16]],"date-time":"2022-08-16T04:56:27Z","timestamp":1660625787000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2022.940377\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,16]]},"references-count":33,"alternative-id":["10.3389\/fonc.2022.940377"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2022.940377","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,16]]},"article-number":"940377"}}