Overcoming Erlotinib Resistance in EGFR Mutation-Positive Non-Small Cell Lung Cancer Cells by Targeting Survivin
Overcoming Erlotinib Resistance in EGFR Mutation-Positive Non-Small Cell Lung Cancer Cells by Targeting Survivin
复制标题
DOI：
10.1158/1535-7163.mct-11-0638
复制
发表时间：
2012-01-01
影响因子：
5.7
通讯作者：
Nakagawa, Kazuhiko
中科院分区：
文献类型：
--
作者：
Okamoto, Kunio;Okamoto, Isamu;Nakagawa, Kazuhiko
最近研究表明，在表皮生长因子受体（EGFR）突变阳性的非小细胞肺癌（NSCLC）中，PTEN的缺失通过激活蛋白激酶AKT而导致对EGFR酪氨酸激酶抑制剂（TKI）的耐药性。我们以前的研究表明，EGFR TKI下调抗凋亡蛋白Survivin的表达有助于EGFR突变阳性NSCLC细胞中EGFR TKI诱导的凋亡。我们现在已经研究了生存素表达在由PTEN缺失诱导的EGFR-TKI抗性中的作用。EGFR-TKI厄洛替尼不影响EGFR突变阳性NSCLC细胞中Survivin的表达或诱导细胞凋亡。通过转染特异性短干扰RNA或暴露于小分子生存素抑制因子YM 155下调生存素可逆转体外细胞对厄洛替尼的耐药性。此外，YM 155和厄洛替尼的联合治疗抑制裸鼠中EGFR突变阳性、PTEN缺陷型NSCLC细胞形成的肿瘤生长的程度大于单独使用任一种药物的治疗。因此，这些结果表明，PTEN缺失诱导的AKT-生存素通路持续激活的信号传导是EGFR突变阳性NSCLC对厄洛替尼诱导的细胞凋亡耐药的机制的基础。他们进一步表明，靶向生存素有可能克服EGFR突变阳性NSCLC中的EGFR-TKI耐药性。Mol Cancer Ther; 11（1）; 204-13. (C)2011年AACR。
Loss of PTEN was recently shown to contribute to resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in EGFR mutation-positive non-small cell lung cancer (NSCLC) through activation of the protein kinase AKT. We previously showed that downregulation of the expression of the antiapoptotic protein survivin by EGFR-TKIs contributes to EGFR-TKI-induced apoptosis in EGFR mutation-positive NSCLC cells. We have now investigated the role of survivin expression in EGFR-TKI resistance induced by PTEN loss. The EGFR-TKI erlotinib did not affect survivin expression or induce apoptosis in EGFR mutation-positive NSCLC cells with PTEN loss. Downregulation of survivin either by transfection with a specific short interfering RNA or by exposure to the small-molecule survivin suppressor YM155 reversed erlotinib resistance in such cells in vitro. Furthermore, combination therapy with YM155 and erlotinib inhibited the growth of tumors formed by EGFR mutation-positive, PTEN-deficient NSCLC cells in nude mice to a greater extent than did treatment with either drug alone. These results thus indicate that persistent activation of signaling by the AKT-survivin pathway induced by PTEN loss underlies a mechanism of resistance to erlotinib-induced apoptosis in EGFR mutation-positive NSCLC. They further suggest that the targeting of survivin has the potential to overcome EGFR-TKI resistance in EGFR mutation-positive NSCLC. Mol Cancer Ther; 11(1); 204-13. (C) 2011 AACR.