2017-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/656142摘要：肺癌為國人癌症發生率及死亡率最高的嚴重疾病, 而在將近50%的東方人肺癌病患中被偵測出其EGFR 基因突變(主要為L858R 以及 exon 19 缺失)且造成EGFR 自體活化。 臨床實驗證實針對EGFR tyrosine kinase domain 設計的臨床用藥- Tyrosine kinase inhibitors (TKIs), 能有效的抑制突變EGFR 的活化並抑制腫瘤生長。 然而大部分對TKIs 有反應的病人卻在治療過後產生抗藥性及新型態的癌症復發,而目前學者已發現約50% TKI-resistant 病人之EGFR amino acid 第790 位置產生第二度的突變(T790M); 另發現有其他基因如 c-Met, Slug, AXL 及Ras..等的活化而使得TKIs 無法因單純抑制EGFR 訊息路徑而抑制腫瘤生長。這是目前臨床上治療肺癌所遭遇莫大的瓶頸。微核苷酸 (miRNAs)是一群內生性的基因表現負調控者, 其特點是單一miRNA 能同時抑制數個基因的蛋白質表達。 而由於miRNAs 為近年來新發現的調控機制,因此細胞中大部分miRNAs 的下游基因及所調控的功能都尚未清楚。因此我們欲建立一個miRNAs 的篩選台, 針對EGFR –T790M 以及因其他致癌基因活化的而產生對TKIs 有抗藥性的不同肺癌型態細胞株, 來篩選在TKIs 存在的情況下,具有抑制腫瘤生長以及對癌症專一性毒殺的miRNAs, 並進一步釐清其下游的調控機制。 除此之外, 我們尚能透過研究miRNAs 及其下游基因來尋找TKIs 形成抗藥性的機制, 並針對這些基因來評估其作為標靶藥物的可能性, 以達到治療新型態肺癌的目的。<br> Abstract: Lung adenocarcinomas that harboring activating mutations in the epidermal growth factor receptor (EGFR,L858R and exon 19 deletions) are initially responsive to small molecule tyrosine kinase inhibitors (TKIs),but the efficacy of these agents is often limited because of the emergence of drug resistance conferred by asecond mutations (T790M or exon 20 mutations) or activation of alternative pathways (c-Met, Slug, AXLand others). Synthetic lethality is a novel promising strategy for specific targeting of cancer cells that carryspecific gene mutations, which are absent in normal cells. This approach may help overcome the challengeof drug resistance that associated with EGFR-TKIs in lung adenocarcinoma.MicroRNAs (miRNAs) are a recently discovered class of endogenous non-coding RNAs that function askey regulators of the human genome. The frequent aberrant expression and functional association ofmiRNAs in many human diseases showed these small cellular components to the preferred drug targets. Inthis proposal, we aim to identify the specific miRNA that can sensitize TKI-resistance lung cancer celllines by overexpression of the inducible miRNAs library from RNAi core. We have previously establishedseveral lung cancer cell lines from NSCLC patients. By using these cell lines, which have different EGFRgenetic backgrounds, as screening templates, we can screen whether their cell viabilities are changed underTKI treatment in each miRNA expression condition. Thus, we may identify the synthetic lethal partner toovercome EGFR-TKI resistance by either acquired resistant mutations or activation of alterative pathways,providing a new therapeutic target of lung cancers.肺癌EGFR鉻胺酸激酶抑制劑( TKIs)微核苷酸 (miRNAs)NSCLCEGFRTKIsmiRNAs