利用高通量RNAi技术研究肺鳞癌EGFR-TKI原发性耐药机制

项目名称： 利用高通量RNAi技术研究肺鳞癌EGFR-TKI原发性耐药机制

项目编号： No.81201706

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 肿瘤学1

项目作者： 鞠立霞

作者单位： 同济大学

项目金额： 23万元

中文摘要： 尽管EGFR-TKI治疗肺腺癌取得了优越的疗效，但其对高表达EGFR基因的肺鳞癌的治疗效果却不理想。肺鳞癌靶点的探索已成为国际研究热点，已发现的新靶基因均为酪氨酸激酶基因，但其阳性率仅3-22%，不足以成为大多数鳞癌的治疗靶点，因此逆转其EGFR-TKI耐药的研究尤为重要。我们前期研究发现肺鳞癌细胞株SK-MES-1高表达EGFR，但对EGFR-TKI耐药,小规模RNAi初筛发现MAPK1受抑后可提高EGFR-TKI敏感性。据此，项目组提出肺鳞癌EGFR-TKI耐药可能与酪氨酸蛋白激酶基因相关的假说。拟采用高通量RNAi技术，沉默肺鳞癌的酪氨酸激酶基因，筛选出最有效逆转肺鳞癌EGFR-TKI耐药的基因，并通过建立稳定转染目的基因siRNA的细胞株及其移植瘤动物模型进行验证及机制探讨，同时检测临床组织中的目的基因水平，评估其作为逆转EGFR-TKI耐药靶点的可能，为肺鳞癌治疗提供新思路。

中文关键词： 肺鳞癌；EGFR-TKI；耐药；高通量；RNAi

英文摘要： Although EGFR-TKI treatment has made a significant effect in lung adenocarcinoma, no remarkable improvement was seen in treatment of squamous cell lung carcinoma with EGFR overexpression. All new targets discovered for lung squamous cell carcinoma are tyrosine kinase gene with a positive rate of 3-22%, which can not be treated as the target for most squamous cell carcinoma. Therefore, it's crucial to reverse EGFR-TKI resistance. Our previous study has found that lung squamous carcinoma cell line SK-MES-1 has high expression of EGFR, and it is resistant to EGFR-TKI. A small-scale RNAi screening has confirmed that the inhibition of MAPK1 can improve the efficacy of EGFR-TKI. So we hypothesize that EGFR-TKI resistance in squamous cell lung cancer may be related to protein tyrosine kinase gene. A High-throughput RNAi technology will be used to screen the most effective gene related to EGFR-TKI resistant in squamous cell carcinoma, and stable transfected cell lines and xenograft models with target gene-siRNA will be established to confirm the result and to explore the related mechanism. At the same time, tumor tissues will be collected to detect the expression of target gene so as to assess its role in reversing resistance of EGFR-TKI. The study may provide new ideas for the treatment of lung squamous cell

英文关键词： lung squamous cell carcinoma；EGFR-TKI；resistance；high-throughput；RNAi