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系統識別號 U0026-0309201315260900
論文名稱(中文) PI3K/mTOR雙重抑制藥物NVP-BEZ235對野生型上皮生長因子受體的非小細胞肺癌細胞之效用
論文名稱(英文) The anti-cancer effect of the dual PI3K/mTOR inhibitor, NVP-BEZ235, on non-small cell lung cancer harboring wild-type EGFR
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 101
學期 2
出版年 102
研究生(中文) 吳鴻昌
研究生(英文) Hung-Chang Wu
電子信箱 gg4125678@gmail.com
學號 S97971086
學位類別 碩士
語文別 中文
論文頁數 56頁
口試委員 指導教授-蘇五洲
指導教授-洪澤民
口試委員-陳玉玲
召集委員-林建中
中文關鍵字 肺癌  野生型上皮生長因子受體野生型  PI3K/AKT/mTOR 
英文關鍵字 lung cancer  wild-type EGFR  PI3K/AKT/mTOR 
學科別分類
中文摘要 了解上皮生長因子受體基因突變在肺癌的角色協助我們正確使用標靶藥物(像gefitinib或erlotinib)。這些藥物用來治療非小細胞肺癌的病人獲得極佳的治療成效及較化學藥物治療少的副作用。但是我們對於野生型上皮生長因子受體的非小細胞肺癌病人的治療除了化學藥物以外,並沒有有效標靶藥物來治療這一族群。因此新標靶藥物的開發及有效治療是被高度期待的。細胞內(Phosphatidylinositide 3-kinases /protein kinase B-AKT/ mammalian target of rapamycin; PI3K/AKT/ mTOR)訊息傳導在多種不同癌症都已證實其高度活躍以及它對腫瘤生成的重要性。我們發現新的PI3K/AKT/ mTOR訊息傳導雙重抑制的標靶藥物-NVP-BEZ235-對野生型上皮生長因子受體的肺癌細胞有比gefitinib更低的IC50。我們在肺癌的細胞株上測試BEZ235的效果及尋找其背後可能的機轉。我們發現BEZ235對所選的肺癌細胞有效,進一步造成cyclinD1/D3的下降而造成細胞生長停滯在G1期;我們也發現BEZ235對突變型上皮生長因子受體的肺癌細胞也有抑制生長的效果而進一步探討原因發現也是造成cyclinD1/D3的下降。再來我們用BEZ235與gefitinib組合治療在同時在EGFR上有L858R及T790M突變的H1975可成功抑制PI3K/mTOR的訊息。用來預測BEZ235效果的指標,在突變型上皮生長因子受體的肺癌細胞是內生性p-EGFR不強而p-AKT/p-S6的表現較強的,NVP-BEZ235的效果會比較好; 但是在野生型的肺癌細胞如果basal p-4EBP1較強的細胞, NVP-BEZ235的效果反而會比較差。雙重抑制藥物BEZ235不論在突變型或野生型都可能透過減少cyclinD1/D3而達成抑制肺癌細胞生長,至於進一步在動物或人類上的效果則有待後續的研究解答。
英文摘要 Despite of great advances in understanding the role of EGFR mutation in non-small cell lung cancer (NSCLC) and the corresponding target therapy, like gefitinib and erlotinib, we still have no effective and less toxic therapy for patients with NSCLC with wild-type EGFR. Activation of phosphoinositide 3-kinase (PI3K)/AKT/ mammalian target of rapamycin inhibitor (mTOR) pathway is a potential target which is highly expressed in many kinds of solid tumors. A novel dual inhibitor, NVP-BEZ235, has been developed, showing good efficacy in blocking the pathway and an outstanding therapeutic effect in cancer growth inhibition. In this study, we investigate the efficacy of NVP-BEZ235 for inhibition of growth in EGFR-wild type NSCLC and the change of background signaling pathway. We find BEZ235 is effective to both of WT-EGFR NSCLC and MT-EGFR NSCLC cell lines, and the decreased cyclinD1/D3 level may cause cancer cells arrested in G1 phase. Besides that, as combining with gefitinib, BEZ235 could suppress signaling of PI3K/mTOR pathway from H1975 harboring L858R and T790M and may help overcome gefitinib-resistance. About biomarkders, we suggest Basal level of p-AKT/p-S6 may predict BEZ235 response in MT-EGFR, but the level of p-4EBP1 may reversely predict the efficacy of BEZ235 in WT-EGFR lung cancer cell lines. Further studies were needed for the evaluation of efficacy of BEZ235 in vivo.
論文目次 中文摘要 1
Abstract 2
誌謝 3
縮寫指引 4
目錄 5
1 背景與研究目標 8
1.1 肺癌(Lung cancer) 8
1.2 野生型上皮生長因子受體的非小細胞肺癌 9
1.3 磷脂酰肌醇激酶/蛋白激酶B/哺乳動物雷帕霉素靶蛋白( PI3K/AKT/ mTOR) 10
1.4 NVP-BEZ235 11
1.5 EGFR-TKI的抗藥性 12
1.6 研究目標(specific aims) 13
2 實驗方法 15
2.1 細胞株 15
2.2 細胞培養 15
2.3 NVP-BEZ235配製 16
2.4 生長抑制濃度試驗 16
2.5 生長試驗 17
2.6 西方墨點法(Western blotting) - 硫酸十二酯鈉聚丙烯醯胺凝膠電泳法(sodium dodecyl sulfate polyacrylamide gel electrophoresis, SDS-PAGE) 17
2.7 細胞週期分析 22
2.8 移除NVP-BEZ235生長試驗 22
3 實驗結果 23
3.1 NVP-BEZ235對正常細胞的生長抑制 23
3.2 NVP-BEZ235對野生型上皮生長因子受體的非小細胞肺癌細胞生長的影響 23
3.3 分析NVP-BEZ235對野生型上皮生長因子受體非小細胞肺癌細胞的訊息變化 24
3.4 分析NVP-BEZ235對野生型上皮生長因子受體非小細胞肺癌細胞株的細胞週期 26
3.5 研究NVP-BEZ235處理後的細胞移除NVP-BEZ235對細胞生長的影響 27
3.6 NVP-BEZ235對mutant-type EGFR的非小細胞肺癌細胞生長的影響 27
3.7 分析NVP-BEZ235對突變型上皮生長因子受體非小細胞肺癌細胞的訊息變化 29
3.8 分析合併NVP-BEZ235和gefitinib對突變型上皮生長因子受體非小細胞肺癌細胞的訊息變化 30
4 討論 32
5 參考文獻 36
表目錄 42
Table 1 細胞株資訊及特性 42
Table 2 NVP-BEZ235藥物在野生型上皮生長因子受體非小細胞肺癌細胞的IC50 43
Table 3 NVP-BEZ235藥物在突變型上皮生長因子受體非小細胞肺癌細胞的IC50 44
圖目錄 45
Figure 1 NVP-BEZ235對正常人類纖維芽細胞的效果 45
Figure 2 NVP-BEZ235藥物在野生型上皮生長因子受體非小細胞肺癌細胞的效果 46
Figure 3 NVP-BEZ235對野生型上皮生長因子受體非小細胞肺癌細胞的生長抑制 47
Figure 4 NVP-BEZ235在野生型上皮生長因子受體非小細胞肺癌細胞對PI3K及mTOR下游訊息的抑制 48
Figure 5 NVP-BEZ235在野生型上皮生長因子受體非小細胞肺癌細胞的訊息改變 49
Figure 6 NVP-BEZ235造成野生型上皮生長因子受體非小細胞肺癌細胞株細胞週期停留在G1期 50
Figure 7 對已用NVP-BEZ235處理過的野生型上皮生長因子受體非小細胞肺癌細胞移除NVP-BEZ235對細胞生長的影響 51
Figure 8 NVP-BEZ235藥物在突變型上皮生長因子受體非小細胞肺癌細胞的效果 52
Figure 9 NVP-BEZ235對突變型上皮生長因子受體非小細胞肺癌細胞的生長抑制 53
Figure 10 NVP-BEZ235在突變型上皮生長因子受體非小細胞肺癌細胞對PI3K及mTOR下游訊息的抑制 54
Figure 11 NVP-BEZ235在突變型上皮生長因子受體非小細胞肺癌細胞的訊息改變 55
Figure 12 NVP-BEZ235合併gefitinib在突變型上皮生長因子受體非小細胞肺癌細胞H1975的訊息改變 56
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