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Barncancerfonden","award":["LA2019-0080"],"award-info":[{"award-number":["LA2019-0080"]}]},{"name":"Swedish Childhood Cancer Foundation, Barncancerfonden","award":["LA2020-0012"],"award-info":[{"award-number":["LA2020-0012"]}]},{"name":"Swedish Childhood Cancer Foundation, Barncancerfonden","award":["LA2021-0019"],"award-info":[{"award-number":["LA2021-0019"]}]},{"name":"Swedish Childhood Cancer Foundation, Barncancerfonden","award":["SLS-934161"],"award-info":[{"award-number":["SLS-934161"]}]},{"name":"Swedish Childhood Cancer Foundation, Barncancerfonden","award":["M20-0061"],"award-info":[{"award-number":["M20-0061"]}]},{"name":"Swedish Childhood Cancer Foundation, Barncancerfonden","award":["M21-0012"],"award-info":[{"award-number":["M21-0012"]}]},{"name":"Swedish Childhood Cancer Foundation, Barncancerfonden","award":["TJ2022-0067"],"award-info":[{"award-number":["TJ2022-0067"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Human papillomavirus positive (HPV+) tonsillar and base of tongue cancer (TSCC\/BOTSCC) is rising in incidence, but chemoradiotherapy is not curative for all. Therefore, targeted therapy with PI3K (BYL719), PARP (BMN-673), and WEE1 (MK-1775) inhibitors alone or combined was pursued with or without 10 Gy and their effects were analyzed by viability, proliferation, and cytotoxicity assays on the TSCC\/BOTSCC cell lines HPV+ UPCI-SCC-154 and HPV\u2212 UT-SCC-60A. Effective single drug\/10 Gy combinations were validated on additional TSCC lines. Finally, APR-246 was assessed on several TSCC\/BOTSCC cell lines. BYL719, BMN-673, and MK-1775 treatments induced dose dependent responses in HPV+ UPCI-SCC-154 and HPV\u2212 UT-SCC-60A and when combined with 10 Gy, synergistic effects were disclosed, as was also the case upon validation. Using BYL719\/BMN-673, BYL719\/MK-1775, or BMN-673\/MK-1775 combinations on HPV+ UPCI-SCC-154 and HPV\u2212 UT-SCC-60A also induced synergy compared to single drug administrations, but adding 10 Gy to these synergistic drug combinations had no further major effects. Low APR-246 concentrations had limited usefulness. To conclude, synergistic effects were disclosed when complementing single BYL719 BMN-673 and MK-1775 administrations with 10 Gy or when combining the inhibitors, while adding 10 Gy to the latter did not further enhance their already additive\/synergistic effects. APR-246 was suboptimal in the present context.<\/jats:p>","DOI":"10.3390\/cancers15010093","type":"journal-article","created":{"date-parts":[[2022,12,27]],"date-time":"2022-12-27T07:31:56Z","timestamp":1672126316000},"page":"93","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Targeted Therapy with PI3K, PARP, and WEE1 Inhibitors and Radiotherapy in HPV Positive and Negative Tonsillar Squamous Cell Carcinoma Cell Lines Reveals Synergy while Effects with APR-246 Are Limited"],"prefix":"10.3390","volume":"15","author":[{"given":"Karin","family":"Byskata","sequence":"first","affiliation":[{"name":"Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, 171 64 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Lukoseviciute","sequence":"additional","affiliation":[{"name":"Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, 171 64 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6967-8387","authenticated-orcid":false,"given":"Filippo","family":"Tuti","sequence":"additional","affiliation":[{"name":"Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, 171 64 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4013-7688","authenticated-orcid":false,"given":"Mark","family":"Zupancic","sequence":"additional","affiliation":[{"name":"Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, 171 64 Stockholm, Sweden"},{"name":"Department of Head-, Neck-, Lung- and Skin Cancer, Theme Cancer, Karolinska University Hospital, 171 64 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ourania N.","family":"Kostopoulou","sequence":"additional","affiliation":[{"name":"Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, 171 64 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Holzhauser","sequence":"additional","affiliation":[{"name":"Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, 171 64 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tina","family":"Dalianis","sequence":"additional","affiliation":[{"name":"Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, 171 64 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","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. 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