Effect of small molecule tyrosine kinase inhibitors on PDGF-AA/BB and PDGFR-α/β-expression in HPV-positive and -negative SCC

Introduction Despite extensive research into new treatment options the prognosis for HNSCC remains poor. The Platelet-derived growth factor (PDGF) family is involved in cancerogenesis and angiogenesis of HNSCC. In this study we investigated the effect of small molecule tyrosine kinase inhibitors (TKI) on the expression of PDGF/PDGFR in vitro using HPV-positive and -negative squamous cancer cell lines.

Materials and methods Two human HPV-negative cell lines (UMSCC-11A/-14C) and one HPV-positive cell line (CERV196) were used. 20 µmol/l of Nilotinib, Dasatinib, Afatinib, Gefitinib and Erlotinib were incubated with the tumor cells for 24-96h. We assessed cell proliferation via a proliferation assay and protein concentrations of PDGF-AA/BB and PDGFR-α/-β via Sandwich ELISA. For statistical analysis we compared the results with an untreated negative control.

Results PDGF-AA/BB and PDGFR-a/-ß were detected in all three tested cell lines. The addition of the tested TKI’s led to a significant (p<0,05) decrease of PDGF/PDGFR at varying 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’s were independent of the HPV-status.

Discussion PDGF is upregulated in HNSCC and expression levels decrease after surgery, suggesting a role in tumor development. The influence of HPV on the PDGF/PDGFR-pathway remains unclear. Our results show that proteins of this pathway can effectively be inhibited by small molecule TKI’s. PDGF-AA seems to be a promising target for future studies with selective TKI’s. Combination therapies should be researched to avoid evasion of targeted therapy by transactivation of other pathways through heterodimeric receptors.

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Publication History

Article published online:
10 June 2020