Bim在介导非小细胞肺癌ALK抑制剂获得性耐药中的机制研究

项目名称： Bim在介导非小细胞肺癌ALK抑制剂获得性耐药中的机制研究

项目编号： No.81201707

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： 任胜祥

作者单位： 同济大学

项目金额： 23万元

中文摘要： 间变淋巴瘤激酶（ALK）抑制剂在具有EML4-ALK基因融合的晚期非小细胞肺癌患者中发挥重要作用，然而耐药已成为其治疗瓶颈，耐药机制尚未阐明。ALK基因活化主要通过Akt、ERK和STAT3通路发挥作用, ALK抑制剂则通过诱导敏感细胞Bim的表达来发生凋亡。我们前期研究发现Crizotinib（ALK抑制剂）诱导敏感细胞株产生Bim的表达，而在耐药珠中并未出现。 我们推测Bim参与了ALK抑制剂使用后的获得性耐药，但具体调控机制有待阐明。因此本课题拟采用基因芯片、基因转染、siRNA、RT-PCR、western bolt等方法在细胞和动物水平探讨Bim与PI3K/Akt、MEK/ERK、JAK/STAT3信号传导通路的关系，明确Bim在ALK抑制剂获得性耐药中的作用和机制,并通过临床标本加以验证，从而进一步阐明ALK抑制剂获得性耐药的分子调控机制，并为逆转耐药提供可能的候选靶点和思路。

中文关键词： 非小细胞肺癌；ALK融合；BIM；获得性耐药；

英文摘要： Anaplastic lymphoma kinase (ALK) inhibito palys an important role in the therapy of advanced NSCLC patients with EML4-ALK genes arrangement, however, resistance has become its treatment bottleneck and resistance mechanisms has not been elucidated. ALK gene is activated primarily through Akt, ERK and STAT3 pathways and ALK inhibitor induces apoptosis in the senstive cells through the expression of Bim . Our previous study found that Crizotinib (a kind of ALK inhibitor) could induced the expression of Bim in the sensitive cell lines while not in the drug-resistant cell lines. Which suggest that Bim participate in the acquired resistance of ALK inhibitor, however, the detailed regulated mechanism is still not so clear. This program used the methods of gene chips、genes transfection、siRNA、RT-PCR and western bolt to investigate the accociation of Bim and PI3K/Akt, MEK/ERK, JAK/STAT3 signal transduction pathways in cell and animal levels, trying to indentify the role and function of Bim in the resistant mechanism of ALK inhibtor. The results got from the above studies will be further verified in the clinical specimens. As a result,this program try to clarify the molocular mechanism of ALK inhibtors and might provide the potiential target and stategy to reversed the resistance of ALK inhibtor.

英文关键词： NSCLC；ALK fusion；BIM；Accquired Resistance；