2014-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/656686摘要：表皮生長因子接受器(EGFR)激活突變之肺腺癌對於酪胺酸激酶抑制劑(tyrosinekinase inhibitors; TKI) 標靶治療抗藥性已經有許多的文獻被研究探討。其中包括 EGFR-T790M突變(~60%)，MET amplification (~5-10%)，PIK3CA mutation (~5%)，BRAF mutation (~1%)及其它未知的機制。最近幾年的研究指出肺線癌轉型小細胞肺癌 (SCLC) (~5%)也是 TKI標靶治療抗藥性的機制之一。在我們的臨床研究中，我們也發現一位 50歲非抽煙女性的 EGFR-L858R激活突變肺腺癌患者。在EGFR-TKI治療失效復發後，利用組織學的檢查中發現其復發的組織切片中癌組織細胞具有小細胞肺癌的特性並且此小細胞肺癌仍然保有 EGFR-L858R突變。我們利用體外細胞培養的方式從這位病人復發時的胸水中成功地建立一細胞株。另人感興趣的是此一細胞株同時具有平貼和懸浮的兩種型態。其中懸浮的細胞大量地表現神經內分泌 (neuroendocrine) 細胞的蛋白質標記而平貼的細胞則沒有。此外我們利用試管外(in vitro)培養外加藥物的方式成功地使得單一細胞株具有型態上的轉變。直至今日，尚未有從肺線癌轉型為小細胞肺癌的細胞株被報導出。因此我們的細胞株為一非常良好的研究材料去探討 SCLC轉型的機制。我們在本篇計畫的研究目標即是利用此細胞株去嘗試找出 EGFR突變之肺腺病人藉由轉型為小細胞肺癌獲得 TKI標靶治療抗藥性的機制。<br> Abstract: Several acquired resistant mechanisms of epidermal growth factor receptor (EGFR) activating mutation of lung adenocarcinoma to EGFR-tyrosinekinase inhibitors (TKIs) therapy have been reported. These mechanisms include EGFR-T790M mutation (~60%), MET amplification (~5-10%), PIK3CA mutation (~5%), BRAF mutation (~1%) and other unknown mechanisms. Most recently, small cell lung cancer (SCLC) transformation (~5%) has been reported as one of resistant mechanisms during EGFR-TKIs treatment in lung adenocarcinoma. Here we describe a patient of 50-year-old non-smoker female with EGFR-L858R activating mutation lung adenocarcinoma. She had initial response to EGFR-TKI, but became resistant after 6 months treatment. After disease progression on EGFR-TKIs treatment, histological examination of a secondary biopsy specimen reveals typical features of SCLC and still harboring EGFR-L858R mutation. We successfully establish the primary cancer cells from progressive pleural effusion of this patient. Interestingly, these cells show two different morphologies, one is suspension cells and the other is attached cells. Suspension cells highly express neuroendocrine marker synaptophysin but attached cells do not. We also successfully trigger morphologies transformation with drugs treatment by single clone cells in vitro. Until now, there is no SCLC transformation cell line harboring EGFR-activating mutation from lung adenocarcinoma patient who acquired EGFR-TKI resistance after treatmenthas been reported previously. Our This cell line is a good modelmaterial to study the mechanism of SCLC transformation from lung adenocarcinoma. The objectives aims in of this study are to find out the mechanisms of EGFR-TKIs resistance through SCLC transformation in lung adenocarcinoma.