非小细胞肺癌EGFR-TKI再治疗反应临床观察及机制探讨

Retreatment of non-small cell lung cancer with EGFR-tyrosine kinase inhibitor

目的:观察非小细胞肺癌(non-small cell lung cancer,NSCLC)患者使用表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitor,EGFR-TKI)初始治疗失败后,经过一段时间的间歇期,再次应用EGFR-TKI治疗的临床疗效,并探讨其可能的分子机制。方法:回顾性分析2008-12-01-2012-05-30,我院19例初始用EGFR-TKI治疗失败后停止一段时间并再次应用EGFR-TKI治疗的NSCLC患者的临床资料。采用小剂量递增的方法,体外诱导EGFR-TKI耐药的细胞模型,研究"治疗再反应"现象可能的分子机制。结果:19例NSCLC患者中47.4%(9/19)再次应用EGFR-TKI仍可获得疾病控制,其中PR为15.8%(3/19),SD为31.6%(6/19)。同时,体外诱导的耐药细胞株经顺铂治疗2个月后,再次给予厄洛替尼(Erlotinib)治疗,抑制率由3%升高至15%,P<0.05,再次显示了部分的有效性。蛋白质印迹法检测自噬相关分子LC3B发现,耐药细胞株LC3B表达增加,再次Erlotinib治疗后LC3B表达水平相对未处理细胞明显下调。结论:EGFR-TKI治疗失败的NSCLC患者经过一段时间的间歇期再次应用EGFR-TKI,部分患者仍可获得较满意的疾病控制,该效应可能与细胞自噬有密切关系,这种再治疗反应有望成为NSCLC的一种有效治疗策略。

OBJECTIVE： To evaluate the efficacy and mechanisms of retreatment with EGFR-TKI in non-small cell lung cancer （NSCLC）. METHODS： Nineteen NSCLC patients who were retreated with EGFR-TKI after failure of the ini- tial EGFR-TKI therapy from December 1st, 2008 to May 30th, 2012 were retrospectively analyzed, and the mechanisms were investigated in vitro. RESULTS： Of the 19 patients who received 2nd EGFR-TKI treatment,the disease control rate was 47.4% （9/19）, 3 patients （15. 8%） showed PR, 6（31. 6O//oo） achieved SD. After being treated with Cisplatin for 2 months,the inhibitory rate of the EGFR-TKI resistant cell line（PER） to the EGFR-TKI raised from 3~/6o to 15~//00 （P~ 0.05）. The expression level of autophagy related molecule LC3B was higher in the PER cell than that in the PC9 cell, while decreased significantly after the retreatment. CONCLUSION： Our results suggest that a 2nd EGFR-TKI treatment can be an effective option for NSCLC patients who experienced treatment failure from their initial use of EGFR-TKI, which may be related to cell autophagy.