获得性耐药是NSCLC靶向治疗的最大障碍。我们前期研究发现MEK/ERK旁路激活导致NSCLC对第三代EGFR-TKI耐药，并且与敏感细胞相比，耐药细胞LKB1表达下调，p-ERK表达上调。研究显示，LKB1缺失可激活FAK/Src。FAK/Src/PXN信号级联反应可磷酸化激活ERK。另有研究显示，Paxillin (PXN)介导的ERK激活导致了NSCLC对第一代EGFR-TKIs耐药。因此，我们推测，LKB1可能通过FAK/Src/PXN信号级联反应调控ERK磷酸化水平，介导NSCLC第三代EGFR-TKI AZD9291耐药。基于上述设想，本项目拟通过细胞水平和动物模型两个方面研究，系统探讨LKB1与FAK/Src/PXN、MEK/ERK信号通路的调控关系及其在第三代EGFR-TKI耐药中的作用，为探索和发现新的耐药机制，以制定有效的治疗策略提供重要理论依据。

Development of acquired resistance to small cancer therapeutic molecules has become a major obstacle in the clinic for a long-term efficacy. We recently reported that modulation of MEK/ERK-dependent Bim and Mcl-1 degradation critically mediates resistance of EGFR-mutant NSCLC cells to AZD9291.And we found that the expression of LKB1 is decreased and p-ERK is increased in AZD9291 resistant NSCLC cells compared to parental sensitive cells. A previous study demonstrated that the nonreceptor tyrosine kinases Src and FAK are activated by LKB1 Loss. PXN is phosphorylated by FAK and Src and in turn binds to other downstream proteins including ERK. Another study showed that Paxillin (PXN)-mediated ERK activation is responsible for 1st generation TKIs resistance. We thus hypothesized that MEK/ERK hyperactivation in a LKB1/ FAK/Src/ PXN dependent pathway may result in resistance to AZD9291. Based on the above ideas, this project tends to use cell culture in vitro and xenograft in nude mice to explore molecular mechanism of resistance to third generation EGFR-TKI in EGFR-mutant lung cancers confered by LKB1 via activating MEK/ERK pathway. The accomplishment of this project will help to deepen the understanding the mechanism of resistance to target therapy in order to develop effective strategies to delay or overcome resistance.