肿瘤微环境介导异质性EGFR突变肺腺癌靶向治疗获得性耐药的分子机制及逆转耐药的策略研究

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) has emerged as an indispensable therapeutic strategy for patients harboring EGFR mutation, bringing significant survival benefit as well as improving the quality of life. In clinical practice, however, these patients could hardly escape from treatment failure 8-12 months later due to acquired resistance, making it the bottleneck that restrains targeted therapies from becoming the curing approach of lung cancer. The current targeted drugs and therapeutic strategies to overcome resistance focus merely on tumor itself while neglecting the host, i.e. the influence of tumor microenvironment on resistance. In this study, we conducted numerous studies in vivo and vitro to explore the interaction pattern between sensitive and resistant subclones of heterogeneous lung cancer during targeted therapy, and to disclose the molecular mechanism of the targeted therapy-induced cell secreting signal network activating the resistant subclone, and to determine the immunogenicity of EGFR-TKI-resistance-related genes in non small cell lung cancer (NSCLC) and the relevance and regulatory mechanism of these genes with vital inhibitory molecules in tumor microenvironment. Further we explored the combined therapeutic strategy aiming at various resistant genes and the corresponding microenvironment changes and established a predictive system based on circulating tumor cells (CTCs), which can provide evidence for the future clinical application combining targeted therapy and immunotherapy.

表皮生长因子受体酪氨酸激酶抑制剂（Epidermal growth factor receptor tyrosine kinase inhibitors, EGFR-TKIs）为突变型肺腺癌患者带来生存和生活质量的受益，已成为其不可或缺的重要治疗方式。但临床实践中，几乎所有EGFR突变患者在治疗有效10个月左右因耐药而治疗失败。故耐药是限制靶向治疗成为肺癌治愈性手段的瓶颈。目前靶向药物及克服耐药的治疗策略仅关注肿瘤因素而忽略宿主因素，即肿瘤微环境对耐药的影响。本研究在前期建立的异质性模型及人群队列基础上，通过体内外试验及组学研究，探讨在EGFR-TKIs治疗过程中，EGFR突变异质性肺腺癌敏感和耐药克隆的相互作用模式以及细胞因子网络和免疫耐受导致EGFR-TKIs耐药的分子机制，通过循环肿瘤细胞探索预测分子标志物并建立预警、监测体系，为将来临床靶向治疗与免疫治疗的联合应用提供依据。

表皮生长因子受体酪氨酸激酶抑制剂（Epidermal growth factor receptor tyrosine kinase inhibitors, EGFR-TKIs）为突变型肺腺癌患者带来生存和生活质量的受益，已成为其不可或缺的重要治疗方式。但临床实践中，几乎所有EGFR突变患者在治疗有效10个月左右因耐药而治疗失败。故耐药是限制靶向治疗成为肺癌治愈性手段的瓶颈。目前靶向药物及克服耐药的治疗策略仅关注肿瘤因素而忽略宿主因素，即肿瘤微环境对耐药的影响。.本研究在前期建立的异质性模型及人群队列基础上，通过体内外试验及组学研究，发现在EGFR-TKIs治疗过程中，EGFR下游通路活化及髓源性抑制细胞引发的免疫抑制是EGFR突变型NSCLC奥西替尼耐药的机制之一；对于携带T790M突变的患者而言，EGFR T790M-cis-L792F突变是另一个耐药机制，并通过一系列细胞和动物实验发现了潜在的逆转耐药的策略。在免疫治疗方面，证实了外周血PD-1+CD8+TCR高多样性的患者（包括EGFR突变和驱动基因阴性者）能获益于免疫治疗；建立了免疫相关指数，证实该指数高者更有可能从PD-1/PD-L1治疗中获得疗效及生存获益。基于外周血建立了bTMB估算模型，发现DNA 损伤修复通路基因变异与肿瘤突变负荷和新生抗原有关，可预测免疫治疗疗效；揭示前置节拍化疗更能激活机体免疫微环境并与后续免疫治疗发挥协同作用；系统比较了免疫联合治疗策略的疗效及安全性，为EGFR突变型、野生型NSCLC患者的免疫治疗模式提供了理论依据。