基于PSPC1/TGF-β1信号通路的黄芪甲苷抑制非小细胞肺癌EGFR-TKI耐药作用机制研究

表皮生长因子受体-酪氨酸激酶抑制剂（EGFR-TKI）是非小细胞肺癌的重要一线治疗手段，但耐药问题严重限制其临床应用。前期研究发现第三代EGFR-TKI Osimeritinib（OSI）耐药细胞发生明显的上皮间质转化（EMT）现象及TGF-β通路激活。PSPC1调控TGF-β1分泌及EMT或是解决耐药问题的潜在突破口。中药黄芪有效成分黄芪甲苷可抑制PSPC1表达和TGF-β1分泌，抑制TGF-β1诱导的EMT，其对OSI耐药的抑制作用及分子机制有待进一步研究。本项目拟以PSPC1/TGF-β1通路为切入点，在转录组测序和生物信息学分析等基础上深入探究该通路在OSI耐药中的作用及黄芪甲苷对该通路介导EMT和耐药的抑制作用与分子机制。相关研究可阐明PSPC1/TGF-β1通路在EGFR-TKI耐药中的治疗价值，亦为黄芪甲苷及中药黄芪在肺癌耐药治疗中的应用奠定基础。

Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) represents an important first-line treatment for patients with non-small cell lung cancer (NSCLC). However, acquired drug resistance seriously hampers the clinical usage of EGFR-TKI. In the present study, we found that the third-generation EGFR-TKI Osimeritinib (OSI) resistant cell exhibited epithelial-mesenchymal transition (EMT) phenomenon and activation of the TGF-β signaling pathway. Regulation of TGF-β1 secretion and EMT via PSPC1 might be a potential breakthrough for addressing the problem of drug resistance. Astragaloside IV (AS-IV), the main active component of Radix Astragali, could inhibit the expression of PSPC1 and secretion of TGF-β1, as well as TGF-β1-induced EMT. The effect and molecular mechanism of AS-IV on resistance of EGFR-TKI OSI remain to be further studied. In this project, the PSPC1/TGF-β1 signaling pathway will be taken as the entry point for further study. Based on the RNA-Seq and bioinformatic analysis, we will further investigate the role of PSPC1/TGF-β1 signaling pathway in acquired resistance of EGFR-TKI OSI, as well as the effect and mechanism of AS-IV on PSPC1/TGF-β1 mediated EMT and acquired resistance of EGFR-TKI OSI. Relative study would clarify the therapeutic potential of PSPC1/TGF-β1 pathway for acquired resistance of EGFR-TKI, and also lay a foundation for the usage of AS-IV and Radix Astragali in treatment of drug resistant lung cancer.