Dual targeting of PI3K and FGFR or CDK4/6 reveals synergistic responses in HPV-positive and HPV-negative oropharyngeal cancer spheroids.

Human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) generally has a better prognosis than HPV-negative (HPV-) OPSCC. Still, chemoradiotherapy does not cure all patients; therefore, novel treatments are needed. In monolayers of HPV+ / - OPSCC CU-OP cell lines, we previously demonstrated that phosphoinositide 3-kinase (PI3K), fibroblast growth factor receptor (FGFR), and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors reduced viability and had synergistic effects when combined. Here, to better simulate the in vivo state, the effects of these inhibitors and cytostatics were assessed in spheroids of HPV+ / - CU-OP cell lines. All spheroids were treated with single administrations of PI3K (BYL719), FGFR (JNJ-42756493), or CDK4/6 (PD-0332991) inhibitors or cisplatin or docetaxel, as well as with combinations of BYL719 with all named drugs. All inhibitors reduced cell viability and growth in all spheroids, especially in CU-OP-2, while the effects of cisplatin and docetaxel were more limited. Combining BYL719 with all other drugs resulted in additive or synergistic effects in CU-OP-2, while corresponding treatments generally required higher doses to reach similar effects in the other cell lines. Interestingly, the high drug sensitivity of CU-OP-2 differed from the observations made in earlier monolayer studies, where CU-OP-20 was the most sensitive cell line, highlighting the importance of using spheroids in drug screenings.