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目的 ：探讨表皮生长因子受体（epidermal growth factor receptor,EGFR）驱动基因突变的非小细胞肺癌患者在EGFR酪氨酸激酶抑制剂（tyrosine kinase inhibitor,TKI）奥希替尼耐药后免疫治疗的效果，以及程序化死亡配体1(programmed cell death ligand 1,PD-L1)表达上调的分子机制。方法：回顾性分析奥希替尼耐药非小细胞肺癌患者接受免疫联合治疗的临床效果。构建奥希替尼耐药非小细胞肺癌细胞株PC9-OR和HCC827-OR，通过MTT和克隆形成实验验证其耐药性。采用Western Blot实验检测耐药细胞中E26转化特异性转录因子1(E26 transformationspecific sequence 1,Ets1)及PD-L1蛋白的表达。在耐药细胞中使用AKT抑制剂（Dactolisib和LY294002），评估AKT通路对Ets1及PD-L1表达的调控作用。分析siRNA干扰Ets1表达结合AKT抑制剂（LY294002）对PD-L1表达的影响。采用免疫组织化学方法检测奥希替尼耐药前后患者石蜡包埋组织中Ets1及PD-L1的表达变化。结果：免疫联合治疗显著延长奥希替尼耐药非小细胞肺癌患者的无进展生存期。PC9-OR及HCC827-OR细胞具有奥希替尼耐药性，其中AKT通路活化，伴随Ets1及PD-L1表达上调。患者耐药后石蜡组织中Ets1和PD-L1的表达升高。结论：奥希替尼耐药引起AKT通路激活，促进Ets1表达上调，进而驱动PD-L1表达增加，增强患者对免疫治疗疗效，为免疫联合治疗提供了理论依据。
Abstract：Objective: To explore the efficacy of immunotherapy in patients with non-small cell lung cancer(NSCLC)whose epidermal growth factor receptor(EGFR) driver gene mutations are resistant to the EGFR tyrosine kinase inhibitor(TKI) osimertinib, and the molecular mechanism underlying the upregulation of programmed cell death ligand 1(PD-L1)expression. Methods: The efficacy of combination immunotherapy in NSCLC patients with acquired resistance to osimertinib was analyzed retrospectively. The osimertinib-resistant cell lines PC9-OR and HCC827-OR were established, and their resistance was validated via MTT and colony formation assays. Western Blot experiment was employed to test the expression of Ets1 and PD-L1 protein in drug-resistant cells. In drug-resistant cells, AKT inhibitors(Dactolisib and LY294002) were used to evaluate the regulatory effect of the AKT pathway on the expression of Ets1 and PD-L1 expression. Analyze the effect of siRNA-mediated inhibition of Ets1 expression combined with the AKT inhibitor(LY294002) on the expression of PD-L1. The expression changes of Ets1 and PD-L1 in the paraffin-embedded tissues of patients before and after osimertinib resistance were detected by immunohistochemical method. Results: Immunotherapy combination treatment significantly prolonged progression-free survival in NSCLC patients with osimertinib resistance. PC9-OR and HCC827-OR cells exhibited resistance to osimertinib, and the AKT pathway was activated accompanied by the upregulation of Ets1 and PD-L1 expression. The expression of Ets1 and PD-L1 in paraffin-embedded tissues increased after drug resistance in patients. Conclusion: Osimertinib resistance leads to the AKT pathway activation, promoting the upregulation of Ets1 expression, which in turn drives an increase in PD-L1 expression, and enhancing the efficacy of immunotherapy for patients and providing a theoretical basis for combined immunotherapy.
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基本信息:
DOI：10.19767/j.cnki.32-1412.2025.06.002
中图分类号:R734.2
引用信息:
[1]缪捷飞,李梅.EGFR-TKI耐药后AKT/Ets1调控PD-L1的表达介导非小细胞肺癌免疫逃逸的机制探究[J].交通医学,2025,39(06):555-560.DOI:10.19767/j.cnki.32-1412.2025.06.002.
基金信息:
南通市卫生健康委员会项目（MS2024017）