EGFR基因突变与吉非替尼的疗效和获得性耐药关系的研究概况

Overview of relationship between EGFR gene mutation and efficacy and acquired drug resistance of gefitinib

肿瘤的分子靶向治疗是近年发展起来的一种全新的治疗手段。吉非替尼(Gefitinib)是晚期非小细胞肺癌(NSCLC)治疗中的第1个靶向药物,具有特异性强,起效快,不良反应少的特点。其作用机制是抑制表皮生长因子受体(EGFR)酪氨酸激酶的活性,阻断EGFR生成信号传递至细胞内,从而抑制肿瘤细胞的异常增生和转移。临床疗效与EGFR基因的突变具有一定的相关性。EGFR基因突变有外显子19碱基缺失,外显子20的点突变或碱基插入突变和外显子21的点突变3种类型。其中外显子20的点突变可能是肿瘤细胞对Gefitinib产生抗药性的原因。EGFR基因的突变在东方人群,女性,腺癌和非吸烟人群中高表达,而且临床应用中已经证实Gefitinib在上述人群中有效率最高。EGFR基因在应用Gefitinib的过程中亦会发生二次突变,这可能是Gefitinib获得性耐药的机制,但亦有研究显示Gefitinib的耐药与药物的转运、EGFR基因的扩增以及信号通路的改变有关,非单一机制能完全解释其耐药性。所以如何利用EGFR来准确预测Gefitinib的有效性,预防和阻止Gefitinib耐药将是今后对EGFR和Gefitinib研究的重点。

The molecule targeted therapy of tumor is a brand new therapy that has developed recently. Gefitinib is the first target drug in the treatment of advanced-stage non-small lung cancer, and has characteristics of high specificity, quick efficacy and low adverse effect. It can inhibit the activity of EGFR PTK（protein tyrosine kinase）to block the transmembrane signal transduction to inhibit the dysplasia and metastasis of tumor cells. There are some relationships between the clinical efficacy and EGFR gene mutation. There are 3 types of EGFR gene mutation： deletion in exon 19, point mutation or insertion in exon 20 and point mutation in exon 21. Point mutation in exon 20 is the most possible cause that tumor ceils are resist ant to gegitinib. EGFR gene mutation has an increased frequency in adenocarcinomas arising in nonsmokers, women, and individuals of oriental, while in the clinical administration, it has been proven that gegitinib shows the highest efficacy within above-mentioned crowd. In the course of gegitinib administration, secondary EGFR gene mu ration can happen, which is a possible mechanism of acquired gegitinib resistance. However, some other researches show that acquired gegitinib resistance relates to drug transport, EGFR gene amplification and the change of signal transduction.and no single mechanism can explain it. So the research emphasis of EGFR and gefitinib is to find out how to prognose the efficacy of gefitinib and to prevent gefitinib resistance using EGFR.