阿法替尼和奥希替尼在EGFR^(19del+T790M+G724S)突变晚期肺腺癌患者中的治疗作用  

Role of afatinib plus osimertinib in the treatment of advanced lung adenocarcinomas with EGFR^(19del+ T790M+ G724S) mutation

作　　者：吕欣[1] 武星 杨思雨 明宗娟[1] 杨拴盈[1] Lyu Xin;Wu Xing;Yang Siyu;Ming Zongjuan;Yang Shuanying(Department of Pulmonary and Critical Care Medicine,Second Affiliated Hospital,Xi'an Jiaotong University,Xi'an 710004,China)

机构地区：[1]西安交通大学第二附属医院呼吸与危重症医学科,西安710004

出　　处：《国际呼吸杂志》2024年第11期1257-1264,共8页International Journal of Respiration

基　　金：国家自然科学基金(82403583);陕西省自然科学基础研究计划(2023-JC-QN-0814);陕西省卫生健康科研基金(2021D042)。

摘　　要：目的探讨阿法替尼和奥希替尼联用在EGFR^(19del+T790M+G724S)突变的晚期肺腺癌患者治疗中的作用。方法本研究为实验研究。选取EGFR^(19del)的人肺腺癌细胞PC-9和H1650, 转染野生型EGFR质粒(pGV492-Flag-EGFR-WT)和突变型EGFR质粒(pGV492-Flag-EGFR-19del+T790M+G724S)。采用不同浓度奥希替尼(0、1、2、4、8、16 μmol/L)、阿法替尼(0、0.5、1、2、4、8 μmol/L)、两药联用处理肺腺癌细胞PC-9^(19del+T790M+G724S)和H1650^(19del+T790M+G724S), CCK-8法检测各组的细胞活力。采用蛋白质印迹法检测转染EGFR野生型和突变型质粒的PC-9、H1650细胞中EGFR、p-EGFR、STAT1和p-STAT1的蛋白表达水平。采用DMSO、奥希替尼、阿法替尼、两药联用分别处理PC-9^(19del+T790M+G724S)和H1650^(19del+T790M+G724S)细胞, 比较不同处理组EGFR、p-EGFR、STAT1和p-STAT1的蛋白表达水平。采用非随机抽样的方法选择2018年10月12日在西安交通大学第二附属医院呼吸与危重症医学科住院, 并确诊为EGFR^(19del)基因突变的1例晚期肺腺癌患者为研究对象, 给予阿法替尼和奥希替尼联合治疗方案, 观察不良反应, 评估疗效。检索2015年1月1日至2024年9月10日中国知网数据库、万方数据库、中华医学期刊全文数据库和PubMed中的相关文献, 总结分析EGFR^(19del+T790M+G724S)突变肺腺癌患者的治疗方案。结果体外实验发现, 经阿法替尼干预48 h后, PC-9^(19del+T790M+G724S)和H1650^(19del+T790M+G724S)细胞的细胞活力降低呈浓度依赖性, 1、2、4、8 μmol/L阿法替尼干预后的细胞活力均较未干预时下降, 差异均有统计学意义(均P<0.001)。联合用药组在不同浓度的奥希替尼干预下的细胞活力均较奥希替尼单药组下降, 差异均有统计学意义(均P<0.001)。与EGFR野生型组相比, EGFR^(19del+T790M+G724S)突变组PC-9、H1650细胞中p-EGFR和p-STAT1蛋白表达水平均升高, 差异均有统计学意义(均P<0.05)。PC-9^(19del+T790M+G724S)细胞中, �Objective:To investigate the efficacy of afatinib plus osimertinib on treating advanced lung adenocarcinomas with epidermal growth factor receptor(EGFR)^(19del+T790M+G724S) mutation.Methods:This was an experimental study.Human lung adenocarcinoma cell lines PC-9 and H1650 with EGFR^(19del) mutation were transfected with wild-type EGFR plasmid(pGV492-Flag-EGFR-WT)and mutant EGFR plasmid(PGV492-Flag-EGFR-19DEL+T790M+G724S).Lung adenocarcinoma cells PC-9^(19del+T790M+G724S) and H1650^(19del+T790M+G724S) were treated with different concentrations of osimertinib(0,1,2,4,8,and 16μmol/L)and afatinib(0,0.5,1,2,and 4,8μmol/L).Cell viability was detected by CCK-8 assay.The protein levels of EGFR,p-EGFR,signal transducer and activator of transcription 1(STAT1)and p-STAT1 in PC-9 and H1650 cells transfected with EGFR wild-type and mutant plasmids were detected by Western blot.PC-9^(19del+T790M+G724S) and H1650^(19del+T790M+G724S) cells were treated with dimethyl sulfoxide(DMSO),osimertinib,afatinib and osimertinib plus afatinib.Protein levels of EGFR,p-EGFR,STAT1 and p-STAT1 in them were compared.A patient with advanced lung adenocarcinoma who was hospitalized in the Department of Respiratory and Critical Care Medicine of the Second Affiliated Hospital of Xi′an Jiaotong University on October 12,2018 and confirmed with EGFR 19del gene mutation was selected as the research object.The patient was treated with afatinib plus osimertinib.Adverse reactions were observed and the treatment effects were evaluated.Related literatures were searched in China National Knowledge Infrastructure Database,Wanfang Database,Chinese Medical Association Journal Database and PubMed from January 1,2015 to September 10,2024,and the treatment methods of lung adenocarcinomas with EGFR ^(19del+T790M+G724S) mutation were analyzed.Results:In vitro experiments showed that the cell viability of PC-9^(19del+T790M+G724S) and H1650^(19del+T790M+G724S) cells decreased in a concentration-dependent manner after 48 hours of afatinib treatment.Cell viability o

关 键 词：肺腺癌 表皮生长因子受体 阿法替尼 奥希替尼 

分 类 号：R734.2[医药卫生—肿瘤]