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。

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.

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