Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth common cancer worldwide and the fifth most common cancer in Taiwan in 2014. Despite various therapeutic strategies were used, the 5-year overall survival rate of locally advanced HNSCC patients is still poor. Thus, investigation of novel therapeutic agents against HNSCC is in urgent need. It was well-characterized that the expression of epidermal growth factor receptor (EGFR) is highly associated with HNSCC pathogenesis and poor prognosis. We recently identified a novel EGFR tyrosine kinase inhibitor (EGFR-TKI), BPR3K007S0, with potent activity against HNSCC growth. In the present study, we aimed to investigate the anticancer functionality and mechanism of action of BPR3K007S0 in EGFR-overexpressing HNSCC cell line, FaDu. Based on cell proliferation assay, BPR3K007S0 is more effective than that of clinical used EGFR-TKI gefitinib (Iressa). BPR3K007S0 inhibited the expression of activated EGFR and its downstream pathway, such as ERK and AKT. Clonogenic assay demonstrated that BPR3K007S0 significantly reduces the colony size without affected colony formation. Cell cycle analysis showed that FaDu cells treated with BPR3K007S0 lead to increase cell cycle arrest in G1 phase without sub-G1 phase appearance. BPR3K007S0 also induced a senescence-associated secretory phenotype in FaDu cells. On the other hand, since EGFR activation is a major cause of metastasis in HNSCC, the anti-metastatic potential of BPR3K007S0 is investigated in FaDu cells. BPR3K007S0 induced mesenchymal-epithelial transition (MET) with upregulation of E-cadherin and downregulation of N-cadherin. The wound healing and transwell invasion assays revealed that cell migration and invasion ability were inhibited by BPR3K007S0. The in vivo study revealed that BPR3K007S0 significantly inhibited tumor and showed better anti-tumor efficacy than that of gefitinib.BPR3K007S0 also reduced the incidence of pulmonary metastasis in the in vivo experimental metastasis model. The number of metastatic pulmonary nodules was significantly reduced in the BPR3K007S0-treated group compared with the control and gefinitib treated group. Taken together, we proposed that BPR3K007S0 is a potent EGFR-TKI and may have a therapeutic benefit in treatment of HNSCC.