PIM-1信号通路在非小细胞肺癌EGFR-TKI获得性耐药中的作用及其分子机制

EGFR敏感性突变阳性的肺癌患者能从EGFR-TKI治疗中显著获益，但最终都会出现耐药，EGFR通路重新活化是获得性耐药的关键因素。PIM-1作为EGFR、PI3K和STAT传导途径的关键激酶和效应分子，是传递细胞增殖和耐药信号的中继站，因而可能在肺癌EGFR-TKI获得性耐药中发挥重要作用。为深入理解PIM-1在EGFR-TKI获得性耐药中的作用及机制，本研究拟运用Tet On慢病毒系统导入耐药基因建立可调控型耐药细胞系，通过调控耐药基因表达，明确在获得性耐药中EGFR、PI3K、c-MET通路对PIM-1的调控作用；通过敲除或过表达PIM-1等关键分子，探讨PIM-1通路在获得性耐药中的作用，利用基因芯片分析PIM-1下游分子交互网络，筛选分子表达谱，并利用肿瘤标本对PIM-1等分子进行临床验证，以期阐明其在EGFR-TKI获得性耐药的分子机制，为克服EGFR-TKI耐药奠定理论基础。

Non-small cell lung cancer patients with sensitizing mutations of EGFR initially respond to epidermal growth factor receptor (EGFR)- tyrosine kinase inhibitors (TKI) invariably will develop progressive disease ultimately because of acquired resistance. The reactivation of EGFR downstream pathway is the key factor of acquired resistance. As the key kinase and effector of EGFR, PI3K/AKT, and STAT signaling pathway, PIM-1 is the intermediator to mediate cellular signals for proliferation and drug resistance, therefore, PIM-1 may play the crucial role in the lung cancer acquired resistance to EGFR-TKI. In order to further understand the mechanism of EGFR-TKI acquired resistance and the function of PIM-1, our project will establish controllable drug resistance cell lines by introducing drug resistance related genes with Tet-On lentivirus system, and to elucidate the controlling function of EGFR, PI3K, and c-met to PIM-1 in the lung cancer cell proliferation and acquird resistance to EGFR-TKI by modulating gene expression. Moreover, we will investigate the function of PIM-1 pathway in acquird resistance to EGFR-TKI by knockdown or overexpression of the key factors, including PIM-1. In addition, we will investigate the cross-talk between PIM-1 downstream factors by gene expression microarray and obtain the molecular expression profile. Moreover, by clinical detection of these important signalling factors, we will clarify the relationship between the factors and prognosis. Taken together, with this project we will further elucidate the molecular mechanism of PIM-1 in lung cancer acquired resistance to EGFR-TKI, and therefore provide the theoretical base for the finding of novel targets of acquired resistance to EGFR-TKI.