EGFR-TKIs通过阻断AKT/β-catenin抑制肺癌干细胞并下调PD-L1在EGFR突变型非小细胞肺癌中表达的机制研究

EGFR突变阳性肺癌患者接受EGFR-TKIs治疗后的获得性耐药问题突出。前期研究发现在EGFR突变阳性肺腺癌中，EGFR-TKIs能够显著抑制肺癌侧群细胞的增殖及比例，同时裸鼠体内能够下调肺癌组织PD-L1的表达，显著抑制移植瘤的生长和体外侵袭能力。进一步还发现吉非替尼抑制Wnt/β-catenin信号通路活化可能是其抑制肺癌侧群细胞的重要分子机制。在本研究中，我们将利用细胞、分子和动物模型等生物学技术，以EGFR突变阳性的非小细胞肺癌为研究对象，深入研究EGFR-TKIs调控肺癌干细胞并下调PD-L1表达的具体分子机制，揭示获得性耐药的产生与Wnt/β-catenin和PD-1/PD-L1信号通路异常活化的相关性，并初步探讨靶向β-catenin联合T细胞免疫应答在逆转EGFR-TKIs获得性耐药中的作用，为临床的治疗和未来开发逆转EGFR-TKIs获得性耐药的分子靶点提供理论依据。

Over the past decade, EGFR tyrosine kinase selective inhibitor (TKI) therapy has been proved to be effective in treating a subset of non-small cell lung cancer (NSCLC) patients bearing somatic EGFR activating mutation and becomes the standard therapy for such patients as first-line therapy. However, although most patients initially respond well, nearly all patients inevitably develop resistance. The β-catenin signaling pathway has been found to be associated with chemoresistance and can activate the EGFR and its downstream pathways. While the EGFR and Wnt/β-catenin signaling systems synergistically regulate many essential developmental and regenerative processes, however, the mechanisms of their cross-talk remain poorly defined. Our previous results showed that the treatment with EGFR-TKIs significantly reduced the cancer stem-like cells (CSCs) in vitro, and also could obviously down-regulated PD-L1 expression and reduced the tumor size in vivo xenograft model. Our further studies indicated that the effect of gefitinib on CSCs phenotypes was mediated through AKT/β-catenin signaling. The aim of our study is to explore the molecular mechanisms of CSCs regulated by EGFR-TKIs based on the phenomenon of the down-regulating of the percentage of CSCs. This study will provide clinical treatment for theory evidence. Taken together, this project will raise an intriguing question of the role of β-catenin and PD-L1 in acquired resistance of EGFR-TKI-treated cancer stem cell-like population(s) and its potential as new treatment strategy for NSCLC in the future.