MET基因是晚期肺腺癌治疗具有潜力的新靶点，克服MET通路耐药非常重要；我们前期研究已发现MET D1246N、Y1248H二个位点突变是部分患者的耐药原因之一；但是对于其它引起耐药突变的分子信号及下游机制尚不清楚。在前期的预实验中，我们发现当MET-TKI出现获得性耐药后，相关AXL基因及相关下游通路Akt、Erk、mTOR通路发生了改变，体内外试验显示具有针对AXL、MET等多靶点的II型MET抑制剂可克服耐药。既往研究中也发现，在MET耐药中发现EGFR或AXL过表达的现象；故假说AXL通过活化EGFR/PKC/mTOR 轴介导MET抑制剂在肺腺癌的耐药，本课题拟通过构建AXL过表达MET耐药模型，通过细胞及小鼠模型验证AXL、EGFR基因对MET抑制剂耐药的作用机制，进一步针对AXL、EGFR及MET下游通路相关靶向药物的药物筛选为进一步寻找及开发新型MET抑制剂提供依据。

MET gene is a new potential target in the treatment of advanced lung adenocarcinoma. So it is urgent to overcome the resistance to MET pathway ; In our previous study, we have found that mutations of MET D1246N, Y1248H are one of the mechanisms of resistance by NGS for MET activation patients before and after treatment with MET-TKI; However, However, the molecular signal and downstream of other resistance mechanisms are not clear, In our previous pre- experiment, we found that when MET-TKI showed acquired resistance, the related Axl gene and related downstream pathways Akt, ERK, mTOR pathway was changed. In vitro and in vivo experiments showed that type II MET inhibitors with multiple targets such as carbozantinib target Axl and MET could overcome the resistance. The other studies have also found that the increase of Axl expression is accompanied by primary or secondary EGFR, PI3K inhibitors, anti HER2 therapy, immune and chemotherapy related resistance. Met and Axl interact in the pathological process of EGFR acquired resistance, and the phenomenon of EGFR or Axl overexpression is also found in MET resistance. Therefore, it is hypothesized that AXL mediates resistance to MET inhibition by activation the EGFR/PKC/mTOR axis in Lung Adenocarcinoma . Therefore, We hypothesized that Axl mediated Met acquired resistance by activating EGFR / PKC / mTOR axis in lung adenocarcinoma. In this study, we intend to construct a MET overexpression model by stimulating MET sensitive cell lines and construct an Axl overexpression MET resistance model by lentivirus transfection technology. We will verify the mechanism of Axl and EGFR genes on MET inhibitor resistance by cell and mouse models, and further test the efficacy of combined therapy for Axl, EGFR and MET related target drugs to further search and development of new MET inhibitors.