TKI耐药的NSCLC患者中20%以上具有c-Met扩增。我们近来研究发现：1)在Gefitinib耐药的肺癌细胞系中，c-Met和TOPK均高表达；2)在恶性肺腺癌临床标本中，TOPK在腺癌中的表达高于癌旁组织；3) c-Met在体外激酶实验中直接磷酸化TOPK；4)在Gefitinib耐药细胞中沉默TOPK，可以促进Gefitinib诱导细胞凋亡。因此，我们提出“c-Met磷酸化TOPK促进NSCLC患者对TKI的耐药” 的假说。我们拟进行如下研究：1.阐明c-Met磷酸化TOPK并调控其功能和稳定性的作用机制；2.在动物实验中进一步验证TOPK抑制剂可以克服肺癌细胞系对TKI的耐药；3.研究TOPK在TKI耐药的NSCLC患者中的表达情况，磷酸化TOPK作为TKI耐药标志物的可能性。研究结果将揭示c-Met-TOPK信号通路在NSCLC中TKI耐药的作用，为解决临床耐药难题提供线索。

c-Met amplification has been observed in over 20% NSCLC patients who are resistant to TKI. Our recent study indicated that:1. Both c-Met and TOPK were highly expressed in TKI resistant lung cancer cell lines; 2. TOPK is highly expressed in malignant lung adenocarcinoma than in matched normal tissues; 3. TOPK was phosphorylated by c-Met directly invitro; 4. Knockdown TOPK in Gefitinib resistant cells promotes apoptosis induced by Gefitinib. Therefore, we hypothesize that “phosphorylation of TOPK by c-Met promotes resistance of TKI in NSCLC patients”. The following experiments will be performed: 1. c-Met phosphorylates TOPK and regulates its function and stability; 2. TOPK inhibitors can overcome TKI resistance in NSCLC patients; 3.Test the expression pattern of TOPK in NSCLC patients and the possibility of TOPK serving as biomarker for TKI resistance and prognosis for NSCLC patients. Reveal of c-Met-TOPK signaling pathway will help understanding further the role of c-Met and TOPK in TKI resistance in NSCLC patients, and provide more clues to overcome this enigma.