RSK2介导Ras/MAPK对PTEN/Akt的调控作用：肠癌EGFR单抗获得性耐药的新机制？

项目名称： RSK2介导Ras/MAPK对PTEN/Akt的调控作用：肠癌EGFR单抗获得性耐药的新机制？

项目编号： No.81502118

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 邹燕梅

作者单位： 华中科技大学

项目金额： 18万元

中文摘要： 针对EGFR的靶向治疗是晚期结直肠癌的主要治疗手段。尽管治疗初期C225等靶向药物显示出较好的临床疗效，但在一年左右时间都不可避免地出现耐药。而这种获得性耐药的分子机制未明。我们前期研究发现C225有效抑制EGFR/Ras/MAPK通路，却伴有Akt激酶活化的现象。进一步研究发现EGFR/Ras/MAPK下游关键激酶RSK2可直接磷酸化PTEN，进而抑制PI3K/Akt通路。据此我们推测：RSK2可能通过介导信号通路间调控机制参与EGFR靶向治疗获得性耐药。本研究将采用基因点突变、LC-MS/MS、基因转录、磷酸化蛋白质组学等方法，多层次系统研究RSK2调控PTEN/Akt的规律，并通过体外细胞和活体动物耐药模型揭示RSK2-PTEN负调控机制与EGFR靶向治疗获得性耐药的相关性，为临床克服肠癌靶向获得性耐药提供新的策略和理论依据。

中文关键词： 结；直肠肿瘤；RSK2；；PTEN/Akt；EGFR单抗；；获得性耐药

英文摘要： The use of anti-EGFR agents such as cetuximab or panitumumab in mCRC has been shown to be successful. For Ras wild type patients who do initially respond to anti-EGFR therapy, the outlook is poor as the efficacy is limited by the devlopment of acquired resistance after one year from the start of therapy. The molecular bases of acquired resistance to anti-EGFR treatment in colorectal cancer are pooly understood. In our previous data, we found that cetuximab could block EGFR/Ras/MAPK activation, but partially restore Akt activity as well. Furthermore, we confirmed that RSK2, a key enzyme downstream in EGFR/Ras/MAPK pathway, could directly phosphorylate PTEN, which in turn jeopardized PI3K/Akt activation. Herein, we hypothesize that EGFR/Ras/MAPK activation may negatively feedback on PI3K/Akt pathway through PTEN phosphorylation by RSK2, which makes contribution to acquired resistance of EGFR-targeted therapies. Our present project utilizes kinds of research strategies to dissect precise molecular mechanisms of the crosstalk of RSK2 on PTEN. Through this angle,we can generate some novel clues for the onset of acquired resistance to anti-EGFR treatment in mCRC and test potential combination strategies to overcome resistance.

英文关键词： colorectal cancer ;RSK2 ;PTEN/Akt;anti-EGFR therapy ;acquired resistance