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Recently, we found synergistic effects by combining the food and drug administration approved (FDA) phosphoinositide 3-kinase (PI3K) and fibroblast-growth-factor-receptor (FGFR) inhibitors BYL719 and JNJ-42756493 on TSCC cell lines. Here this approach was extended and Cyclin-Dependent-Kinase-4\/6 (CDK4\/6) and Poly-ADP-ribose-polymerase (PARP) and WEE1 inhibitors PD-0332991, and MK-1775 respectively were also examined. HPV+ CU-OP-2, -3, -20, and HPV\u2212 CU-OP-17 TSCC cell lines were treated with either BYL719 and JNJ-42756493, PD-0332991 BMN-673 and MK-1775 alone or in different combinations. Viability, proliferation, and cytotoxicity were followed by WST-1 assays and the IncuCyte S3 Live\u00ae Cell Analysis System. All inhibitors presented dose-dependent inhibitory effects on tested TSCC lines. Synergy was frequently obtained when combining CDK4\/6 with PI3K inhibitors, but only sometimes or rarely when combining CDK4\/6 with FGFR inhibitors or PARP with WEE1 inhibitors. To conclude, using CDK4\/6 with PI3K or FGFR inhibitors, especially PD-0332991 with BYL719 presented synergy and enhanced the decrease of viability considerably, while although dose dependent responses were obtained with PARP and WEE1 inhibitors (BMN-673 and MK-1775 resp.), synergy was rarely disclosed.<\/jats:p>","DOI":"10.3390\/v14071372","type":"journal-article","created":{"date-parts":[[2022,6,23]],"date-time":"2022-06-23T22:43:00Z","timestamp":1656024180000},"page":"1372","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Targeted Therapy of HPV Positive and Negative Tonsillar Squamous Cell Carcinoma Cell Lines Reveals Synergy between CDK4\/6, PI3K and Sometimes FGFR Inhibitors, but Rarely between PARP and WEE1 Inhibitors"],"prefix":"10.3390","volume":"14","author":[{"given":"Ourania N.","family":"Kostopoulou","sequence":"first","affiliation":[{"name":"Department of Oncology-Pathology, Karolinska Institute, 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 Institute, 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"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1397-4982","authenticated-orcid":false,"given":"Mariona","family":"Pont","sequence":"additional","affiliation":[{"name":"Department of Oncology-Pathology, Karolinska Institute, Karolinska University Hospital, 171 64 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Papin","sequence":"additional","affiliation":[{"name":"Department of Oncology-Pathology, Karolinska Institute, 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 Institute, Karolinska University Hospital, 171 64 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Borja Agirre","family":"Mikelarena","sequence":"additional","affiliation":[{"name":"Department of Oncology-Pathology, Karolinska Institute, 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 Institute, 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 Institute, Karolinska University Hospital, 171 64 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1002\/1097-0215(20000520)89:3<300::AID-IJC14>3.0.CO;2-G","article-title":"Human Papillomavirus (Hpv) DNA in Tonsillar Cancer: Clinical Correlates, Risk of Relapse, and Survival","volume":"89","author":"Mellin","year":"2000","journal-title":"Int. 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