Effect of Small-molecule Tyrosine Kinase Inhibitors on PDGF-AA/BB and PDGFRα/β Expression in SCC According to HPV16 Status

Abstract

Background: Despite extensive research into new treatment options, the prognosis for head and neck squamous cell carcinoma remains poor. Platelet-derived growth factor (PDGF) is up-regulated in HNSCC and expression levels decrease after surgery, suggesting its role in tumour development. The influence of HPV on the PDGF/PDGF receptor (PDGFR) pathway remains unclear. In this study, we investigated the effect of small-molecule tyrosine kinase inhibitors (TKIs) on the expression of PDGF and its receptor in vitro using squamous cancer cell lines with different human papillomavirus 16 (HPV16) status. Materials and Methods: Two human HPV16-negative cell lines (UMSCC-11A/-14C) and one HPV16-positive cell line (CERV196) were used. Tumour cells were incubated with 20 μmol/l of TKIs nilotinib, dasatinib, afatinib, gefitinib and erlotinib for 24-96 h. Cell proliferation was assessed via proliferation assay and protein concentrations of PDGF-AA and BB and PDGFRα and -β via sandwich enzyme-linked immunosorbent assay. For statistical analysis, the results were compared with those from an untreated negative control. Results: PDGF-AA/BB and PDGFRα/-β were detected in all three tested cell lines. The addition of TKI led to a significant (p<0.05) decrease of PDGF/PDGFR at different time points and cell lines. The strongest effects were seen for the expression of PDGF-AA, which was consistently inhibited by most drugs. The effects of the TKI were independent of the HPV status. Conclusion: Proteins of this pathway can effectively be inhibited by small molecule TKIs. PDGF-AA seems to be a promising target for future studies with selective TKIs.