2014年全球常見癌症的統計中,頭頸部鱗狀細胞癌排名第六名,且位居台灣常見癌症當中的第五名。儘管治療的方法很多,其五年存活率依舊非常低;因此,開發新穎之頭頸部鱗狀細胞癌治療藥物有其迫切性。先前研究指出,表皮生長因子接受器 (EGFR) 的表現量和頭頸部鱗狀細胞癌的病理發展、以及預後息息相關。我們近來發現一種新穎的EGFR酪胺酸激酶抑制劑 (EGFR-TKI) - BPR3K007S0,在頭頸部鱗狀細胞癌中具有抑制腫瘤細胞生長的潛能。本研究目標擬探討在EGFR過度表現的頭頸部鱗狀細胞癌FaDu細胞中,BPR3K07S0抗癌的作用及機制。研究結果顯示,BPR3K007S0對FaDu細胞的生長抑制效果比已知的EGFR-TKI - gefinitib來的好。BPR3K007S0也可抑制EGFR、以及其下游路徑的活化,如ERK及AKT等。細胞群落形成實驗顯示,BPR3K007S0可明顯降低細胞生長的能力,但不影響細胞群落數目;此外,BPR3K007S0不會誘導sub-G1的產生,但會造成細胞停滯在G1期並改變G1期相關調控蛋白的表達。進一步探討發現,BPR3K007S0誘導癌細胞的生長抑制可能與促使細胞老化有關。由於EGFR活化亦是造成頭頸部鱗狀細胞癌惡性轉移的主因之一,因此我們進一步探討BPR3K007S0在FaDu細胞上抗腫瘤惡性轉移的能力。結果顯示,BPR3K007S0可誘發間質-上皮細胞轉換,且會增加E-cadherin和減少N-cadherin的表現量。從細胞刮傷試驗及細胞侵入試驗發現,BPR3K007S0確實可抑制癌細胞遷移及侵襲的活性。進一步在活體動物實驗中驗證,BPR3K007S0確實可以有效抑制FaDu異種移植腫瘤之生長,且其抗腫瘤生長效率比gefitinib佳。此外,小鼠實驗性腫瘤轉移模式也顯示,BPR3K007S0確實可以有效降低FaDu轉移到肺臟的機率,且有投予BPR3K007S0藥物治療的小鼠,其肺部腫瘤節結顯著比沒有投予藥物及投予gefitinib的組別少。綜此,本研究闡明新穎之表皮生長因子接受器酪胺酸激酶抑制劑BPR3K007S0,對EGFR過量表達之頭頸癌的治療有良好的效果,值得進一步臨床治療之運用。
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.