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目的:总结近年来有关非小细胞肺癌(non-small cell lung cancer,NSCLC)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)获得性耐药相关分子机制的研究进展。方法:应用CNKI和PubMed数据库检索系统,以“非小细胞肺癌、EGFR-TKIs和获得性耐药”等为关键词,检索2005-01-2013-06相关文献,共检索到202条文献,纳入标准:1)公开发表和未公开发表的一次文献;2)文章内容提示有EGFRTKIs获得性耐药的基础与临床研究报道;3)分析资料完整,至少有1个对照组;4)研究中有一定含量的样本,并进行统计学分析。剔除标准:1)无对照组文献;2)统计方法不恰当;3)重复报告。最后纳入分析30篇文献。结果:靶向治疗在NSCLC的治疗中取得了明显疗效。一线使用EGFR-TKIs的患者的总生存期可达2年。但即使对于EGFR-TKIs高度敏感的患者,在经过中位生存期7~9个月之后也会发生获得性耐药,主要机制有EGFR第二位点T790M二次突变以及MET的扩增等。目前针对这些机制有很多新药,如BIBW 2992、ARQ 197和克唑替尼等,但其有效率及安全性等仍处于探索阶段。结论:NSCLC患者对EGFR-TKIs获得性耐药机制仍在不断探索中,目前针对其机制的新型抑制剂的多项临床实验也正在进行。
OBJECTIVE: To summarize recent progress in acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC) Research Progress on Related Molecular Mechanisms. Methods: Using CNKI and PubMed database search system, the key words of “non-small cell lung cancer, EGFR-TKIs and acquired drug resistance” were retrieved from 2005-01-2013-06, and 202 articles were retrieved , Inclusion criteria: 1) Published and unpublished literature; 2) The content of the article suggests basic and clinical studies reporting acquired resistance to EGFRTKIs; 3) A complete analysis of the data, with at least 1 control group; 4) In a certain amount of samples, and for statistical analysis. Exclusion criteria: 1) no reference group literature; 2) inappropriate statistical methods; and 3) duplicate reports. Finally included in the analysis of 30 documents. Results: Targeted therapy has achieved significant efficacy in the treatment of NSCLC. Patients with first-line EGFR-TKIs have an overall survival of up to 2 years. However, even in patients highly sensitive to EGFR-TKIs, acquired resistance occurs after a median survival of 7 to 9 months, mainly due to the secondary mutation of T790M at the second site of EGFR and the amplification of MET. Currently there are many new drugs targeting these mechanisms, such as BIBW 2992, ARQ 197 and crizotinib, but their efficiency and safety are still in the exploratory stage. CONCLUSIONS: Acquired resistance mechanisms of EGFR-TKIs in NSCLC patients are still being explored. At present, a number of clinical trials of new inhibitors targeting their mechanism are under way.