FGF-2信号通路介导EGFR-TKIs快速获得性耐药的分子机制研究

项目名称： FGF-2信号通路介导EGFR-TKIs快速获得性耐药的分子机制研究

项目编号： No.81201812

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： 赵琼

作者单位： 浙江大学

项目金额： 23万元

中文摘要： 新近研究显示FGF-2通路作为一条酪氨酸激酶受体信号途径，可促使NSCLC细胞在1-2天内产生针对靶向治疗的"快速获得性耐药"。本课题组在两种NSCLC细胞株中添加EGFR-TKI后, 发现不仅细胞内的EGFR表达被阻断，还出现FGFR2蛋白和mRNA的表达上调，初步证实FGF-2信号可在部分NSCLC细胞株中被EGFR-TKI激活，但其介导耐药的具体作用机制亟需进一步明确。本研究拟继续在NSCLC细胞株中进一步诱导出针对EGFR-TKI的快速获得性耐药状态；以细胞的增殖、凋亡、侵袭和耐药相关分子标记的突变情况为观察指标，评估其耐药情况，并以aRNA芯片技术对一系列下游信号分子进行检测，筛选出相关的信号分子蛋白，以阐明FGF-2信号通路介导EGFR-TKI快速获得性耐药的分子通路机制，拓展肿瘤"快速获得性耐药"这一全新领域的研究，并发现新的抗肿瘤作用靶点。

中文关键词： 非小细胞肺癌；EGFR-TKI 耐药；成纤维生长因子2；细胞模型；高通量芯片

英文摘要： Recent evidence indicated that FGF-2 pathway, as a tyrosine kinases receptor signaling transduction pathway, may be involved in "rapidly acquired resistance to target therapy" in NSCLC cell lines within 1 to 2 days. We investigated the effect of EGFR-TKI on two NSCLC cell lines, and the result revealed the blockage of EGFR as well as the up-regulations of FGFR2 protein and mRNA. Thus, it seems that FGF-2 singaling might be activated by EGFR-TKI in a certain types of NSCLC cell lines, however, the mechanism of FGF-2 in mediating drug-resistance is almost unknown and needs a further elucidation. We plan to continue the investigation by inducing the rapidly acquired resistance to EGFR-TKI in NSCLC cell lines, and evaluate the resistance status using indexes such as cell proliferation, cell apoptosis, cell invasion and resistance-associated molecular mutations. The downstream signal molecules are to be investigated by aRNA array so that key molecules could be detected. Thus, the study will unveil the molecular mechanism of FGF-2 signaling in mediating rapidly acquired resistance to EGFR-TKI, and supply interesting new insights into the whole-new oncology field in rapidly acquired resistance, and discover novel anti-tumor targets.

英文关键词： Non-small cell lung cancer (NSCLC)；Resistance to EGFR-TKI；Fibroblast growth factor 2 (FGF-2)；Cell model；Microarray chip