非小细胞肺癌ERβ诱导SOX17+内皮细胞促进EGFR-TKI抵抗的研究

不同性别NSCLC患者间EGFR突变率及TKI治疗反应存在差异，但雌激素在其中的作用不明。肿瘤细胞耐药突变及旁路激活是EGFR-TKI抵抗的重要原因，而微环境影响的研究还很少。申请人前期研究证实雌激素作用参与NSCLC微环境的调节；通过EGFR突变患者临床队列及单细胞测序数据分析则发现，雌激素受体β(ERβ)表达与EGFR-TKI抵抗相关，并且SOX17+内皮细胞在耐药病灶中显著增多。在此基础上申请人推测，NSCLC细胞ERβ可能通过诱导SOX17+内皮细胞促进EGFR-TKI抵抗。本研究拟综合运用细胞及分子生物学方法，结合转基因动物模型，探索SOX17+内皮细胞的转录调控机制及对EGFR-TKI治疗反应的调节，以及ERβ诱导SOX17+内皮细胞的作用和对非小细胞肺癌EGFR-TKI抵抗的影响。本研究的开展将加深EGFR-TKI抵抗机理的认识，并为解决这一临床问题提供新的思路和治疗靶点。

There are differences in EGFR mutation rates and TKI response among NSCLC patients of different genders, but the role of estrogen is unclear. Drug-resistant mutations and bypass activation of tumor cells are important causes of EGFR-TKI resistance, but the effect of microenvironment is rarely studied. The applicant's previous studies have confirmed that estrogen is involved in the regulation of NSCLC microenvironment. The expression of estrogen receptor β(ERβ) was associated with EGFR-TKI resistance, and SOX17+ endothelial cells were significantly increased in the resistant lesions. On this basis, the applicant speculated that NSCLC ERβ might promote EGFR-TKI resistance by inducing SOX17+ endothelial cells. In this study, cell and molecular biological methods were combined with transgenic animal models to explore the transcriptional regulation mechanism of SOX17+ endothelial cells and its regulation of EGFR-TKI treatment response, as well as the effect of ERβ on induction of SOX17+ endothelial cells and EGFR-TKI resistance in non-small cell lung cancer. This study will deepen the understanding of EGFR-TKI resistance mechanism, and provide new ideas and therapeutic targets for solving this clinical problem.