支架蛋白Aki1作为K-Ras突变大肠癌治疗新靶向的研究

项目名称： 支架蛋白Aki1作为K-Ras突变大肠癌治疗新靶向的研究

项目编号： No.81201961

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2

项目作者： 李琦

作者单位： 南方医科大学

项目金额： 23万元

中文摘要： EGFR在肿瘤发生发展中起到重要作用。EGFR抑制剂（易瑞沙等）和抗体（爱必妥等）已在肺癌、大肠癌、头颈部肿瘤等的临床治疗中显示了良好的效果，然而易瑞沙的获得性耐药和K-ras突变导致的爱必妥耐药阻碍了此类药物的应用和效果。申请人已经报道了肝细胞生长因子导致肺癌对易瑞沙耐药，并报道了EGFR下游支架蛋白Aki1作为肺癌治疗的新靶点的可能性。本项目旨在探讨Aki1在大肠癌治疗中的作用。初步实验表明沉默Aki1基因可导致大肠癌细胞凋亡，不同于EGFR的是，这一作用不受K-ras突变的影响。上述发现提示Aki1或许是K-ras突变大肠癌治疗的新靶点。本项目拟采用基因转染、沉默、小鼠肿瘤模型以及组织标本染色等技术，旨在获得Aki1作为大肠癌新靶向的可靠证据，进一步揭示Aki1与EGFR以及k-ras间的关系，为开发新的靶向药物提供科学依据。

中文关键词： Aki1；K-ras 突变；信号通路；c-Raf；

英文摘要： Epidermal growth factor receptor (EGFR) has been proved to play a important role in tumorigenesis, growth, and suvival. Anti-EGFR using EGFR inhibitor (gefitinib) and/or EGFR antibody (cetuximab) have been widely utilized in clinical therapy of non-small cell lung cancer, colon cancer, head-and-neck cancer, etc. However, acquired resistance to EGFR inhibitors and K-ras mutation related resistance to cetuximab are serious problems for these reagents. Therefore, it is urgent to understand the resistant mechanism, thereby develop new reagents to overcome the drug resistance. We have reported that hepatocyte growth factor (HGF) induces gefitinib resistance in lung cancer with EGFR activating mutations. More recently, we showed that EGFR downstream scaffold protein, Aki1 could be a novel target for lung cancer, even if the lung cancer cells have developed T790M second mutation and became resistance to EGFR inhibitors. In the present study, we further explored the role of Aki1 in colon cancer. Our primary experiments showed that Aki1 was expressed in most of colon cancer cell lines. In contrast to EGFR, deletion of Aki1 by siRNA successfully induced apoptosis of colonl cancer cells even in the presence of K-ras mutation. These results suggested that Aki1 is a novel therapeutic target for colon cancer. In our project,

英文关键词： Aki1；K-ras mutation；signaling pathway；c-Raf；