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

SIMPLE SUMMARY: Human papillomavirus positive tonsillar and base of tongue cancers are rising in incidence but chemoradiotherapy has not improved survival, so novel treatments are needed. Therefore, targeted therapy with phosphoinositide 3-kinase, poly-ADP-ribose-polymerase, and WEE1 inhibitors was pursued alone or combined with/without radiotherapy or using APR-246 and their effects were analyzed by WST-1 viability, proliferation, and cytotoxicity assays on tonsillar and base of tongue cancer cell lines. All three inhibitors induced dose dependent inhibition of viability and proliferation and their effects were enhanced by adding irradiation or by combining the inhibitors. However, adding irradiation to already synergistic inhibitor combinations did generally not induce additional inhibitory effects. Only very high APR-246 doses decreased viability, so its use was limited in this context. To conclude, the effects of the inhibitors were frequently enhanced by adding radiotherapy or by combining them, but adding radiotherapy to the latter did not generally induce further inhibition. ABSTRACT: 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(−) 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(−) 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(−) 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.