靶向EGFR的小分子抑制剂，吉非替尼和厄洛替尼等，虽已成功应用于临床肿瘤的治疗，但长期疗效并不令人满意，主要原因是该类药物耐受性的发生。我们前期研究发现，低分子量肝素联合吉非替尼能够有效抑制吉非替尼耐药NSCLC生长和迁移，我们采用全蛋白质组学和网络药理学方法证实，其可以下调鸟苷酸交换因子DOCK1。因此，本项目中我们拟通过已建立的具有吉非替尼预后数据的NSCLC患者癌组织（人）、EGFR-TKI耐药细胞系（细胞）和裸鼠异种移植模型（动物），确定DOCK1在EGFR-TKI耐药中的关键作用，并阐明其Rac1-GTP激活、EGFR信号途径的串话调节（cross talk）、细胞骨架调节及蛋白-蛋白相互作用的分子机制。此外，应用CADD法寻找DOCK1的小分子抑制剂。为探索新的EGFR-TKI耐药治疗靶点和研发新的治疗EGFR-TKI耐药候选药物提供理论依据和实验数据。

Gefitinib is widely used for the treatment of non-small cell lung carcinoma in patients with sensitizing epidermal growth factor receptor mutations, but patients tend to develop resistance after an average of 10months. In our previous research, we found low molecular weight heparin combined with gefitinib can effectively inhibit cell growth and migration of gefitinib-resistant NSCLC, and one of the key drug targets is dedicator of cytokinesis 1 (DOCK1). Therefore, in the present study, we will clarify the key role of DOCK1 in tumor growth, invasion and migration of gefitinib-resistant NSCLC by using cancer tissue of NSCLC patients treated with gefitinib, EGFR-TKI resistant NSCLC cell lines, and xenograft nude mice model. And more, we will illuminate its Rac1-GTP activation, cross talk with EGFR signal pathway, cytoskeleton regulation and protein-protein interaction network. Further, we try to find DOCK1 DHR2 domain inhibitor by using computer drug virtual screening method and verify by biological experiments. This project will explore key therapeutic target and find effective lead compounds of EGFR-TKI resistant NSCLC. This will provide rational and effective evidence for the treatment of EGFR-TKI resistant NSCLC.