Fibroblast Supernatants Modulate Treatment Responses in Human Papillomavirus Positive and Negative Oropharyngeal...

Human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) has a better outcome than HPV-negative (HPV-) OPSCC, but not all are cured with chemoradiotherapy, thus new therapies are required. Recently, we showed that e.g., phosphoinositide 3-kinase (PI3K) and fibroblast growth factor receptor (FGFR) inhibitors reduced viability in both HPV⁺ and HPV^- OPSCC cell lines. Here, to better mimic the in vivo environment, the effects of supernatants of a normal fibroblast cell line on the responses of HPV⁺/HPV^- OPSCC cell lines to various drugs were examined.

HPV⁺ (CU-OP-2, CU-OP-20) and HPV^- (CU-OP-17) OPSCC cell lines were treated for 72 h with PI3K (BYL719), FGFR (JNJ-42756493), cyclin-dependent kinase (CDK) 4/6, (PD-0332991) and AKT (AZD-5363) inhibitors as well as cisplatin and docetaxel, with/without supernatants from the normal BJ-hTERT fibroblast, or the cancer-associated fibroblast (CAF) KS35 cell lines. Effects on viability and cell confluence/proliferation were then analyzed.

All drugs abrogated viability and confluence in all cell lines. Combining BJ-hTERT cell supernatants with BYL719, JNJ-42756493 and PD-0332991 ameliorated their potential to reduce viability in some cell lines, while this was not the case for AZD-5363 and cisplatin. Docetaxel-induced cell death was only slightly affected, and only in CU-OP-20 cells. BJ-hTERT cell supernatants mainly had analogous effects on confluence to those observed on viability. CAF supernatants had more variable results due to the influence of growth factors needed and added to their media and were not pursued further.

Co-administering fibroblast BJ-hTERT cell supernatants with BYL719, JNJ-42756493, and PD-0332991 had an inhibitory effect on their effects on viability and confluence in some cell lines. This was never the case with cisplatin, and very rarely the case with docetaxel or AZD-5363.