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首页> 外文期刊>Molecular cancer therapeutics >Inhibition of ABCB1 Overcomes Cancer Stem Cell-like Properties and Acquired Resistance to MET Inhibitors in Non-Small Cell Lung Cancer
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Inhibition of ABCB1 Overcomes Cancer Stem Cell-like Properties and Acquired Resistance to MET Inhibitors in Non-Small Cell Lung Cancer

机译:ABCB1的抑制克服了癌症干细胞样特性并获得了非小细胞肺癌中的抑制剂的抗性

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摘要

Patients with non-small cell lung cancer (NSCLC) EGFR mutations have shown a dramatic response to EGFR inhibitors (EGFR-TKI). EGFR T790M mutation and MET amplification have been recognized as major mechanisms of acquired resistance to EGFR-TKI. Therefore, MET inhibitors have recently been used in NSCLC patients in clinical trials. In this study, we tried to identify the mechanism of acquired resistance to MET inhibitors. We analyzed the antitumor effects of two MET inhibitors, PHA-665752 and crizotinib, in 10 NSCLC cell lines. EBC-1 cells with MET amplification were the only cells that were sensitive to both MET inhibitors. We established PHA-665752-resistant EBC-1 cells, namely EBC-1R cells. Activation of KRAS, EGFR, and FGFR2 signaling was observed in EBC-1R cells by FISH and receptor tyrosine kinase phosphorylation antibody arrays. EBC-1R cells also showed overexpression of ATP-binding cassette subfamily B member 1 (ABCB1) as well as phosphorylation of MET. EBC-1R cells grew as cell spheres that exhibited cancer stem cell-like (CSC) properties and epithelial-mesenchymal transition (EMT). The level of miR138 that targeted ABCB1 was decreased in EBC-1R cells. ABCB1 siRNA and the ABCB1 inhibitor elacridar could reduce sphere numbers and suppress EMT. Elacridar could also reverse resistance to PHA-665752 in EBC-1R cells. Our study demonstrated that ABCB1 overexpression, which was associated with CSC properties and EMT, was involved in the acquired resistance to MET inhibitors. Inhibition of ABCB1 might be a novel therapeutic strategy for NSCLC patients with acquired resistance to MET inhibitors. (C) 2015 AACR.
机译:非小细胞肺癌(NSCLC)EGFR突变的患者显示出对EGFR抑制剂(EGFR-TKI)的显着反应。 EGFR T790M突变和满足扩增已被认为是获得EGFR-TKI抗性的主要机制。因此,最近在临床试验中用于NSCLC患者的Met抑制剂。在这项研究中,我们试图确定获得抑制剂的获得性抗性的机制。我们分析了两个Met抑制剂,PHA-665752和Crizotinib的抗肿瘤效应,在10个NSCLC细胞系中。具有达到相扩增的EBC-1细胞是唯一对符合适当抑制剂敏感的细胞。我们建立了PHA-665752抗性EBC-1细胞,即EBC-1R细胞。通过鱼和受体酪氨酸激酶磷酸化抗体阵列在EBC-1R细胞中观察KRAS,EGFR和FGFR2信号传导。 EBC-1R细胞还显示出ATP结合盒亚家族B成员1(ABCB1)的过表达以及满足的磷酸化。 EBC-1R细胞随着表现出癌症干细胞样(CSC)性质和上皮 - 间充质转换(EMT)的细胞球体。靶向ABCB1的miR138水平在EBC-1R细胞中降低。 ABCB1 siRNA和ABCB1抑制剂ELACRIDAR可以减少球形数字并抑制EMT。 Elacridar还可以在EBC-1R细胞中逆转对PHA-665752的抗性。我们的研究表明,与CSC性质和EMT相关的ABCB1过表达参与了所获得的抗性抑制剂。 ABCB1的抑制可能是一种新的NSCLC患者对满足抑制剂的抗性患者的新疗效策略。 (c)2015年AACR。

著录项

  • 来源
    《Molecular cancer therapeutics》 |2015年第11期|共8页
  • 作者单位

    Nippon Med Sch Grad Sch Med Dept Pulm Med &

    Oncol Bunkyo Ku Tokyo 1138603 Japan;

    Nippon Med Sch Grad Sch Med Dept Pulm Med &

    Oncol Bunkyo Ku Tokyo 1138603 Japan;

    Nippon Med Sch Grad Sch Med Dept Pulm Med &

    Oncol Bunkyo Ku Tokyo 1138603 Japan;

    Nippon Med Sch Grad Sch Med Dept Pulm Med &

    Oncol Bunkyo Ku Tokyo 1138603 Japan;

    Nippon Med Sch Grad Sch Med Dept Pulm Med &

    Oncol Bunkyo Ku Tokyo 1138603 Japan;

    Nippon Med Sch Grad Sch Med Dept Pulm Med &

    Oncol Bunkyo Ku Tokyo 1138603 Japan;

    Nippon Med Sch Grad Sch Med Dept Pulm Med &

    Oncol Bunkyo Ku Tokyo 1138603 Japan;

    Nippon Med Sch Grad Sch Med Dept Pulm Med &

    Oncol Bunkyo Ku Tokyo 1138603 Japan;

    Nippon Med Sch Grad Sch Med Dept Pulm Med &

    Oncol Bunkyo Ku Tokyo 1138603 Japan;

    Nippon Med Sch Grad Sch Med Dept Pulm Med &

    Oncol Bunkyo Ku Tokyo 1138603 Japan;

    Nippon Med Sch Grad Sch Med Dept Pulm Med &

    Oncol Bunkyo Ku Tokyo 1138603 Japan;

    Nippon Med Sch Grad Sch Med Dept Pulm Med &

    Oncol Bunkyo Ku Tokyo 1138603 Japan;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 肿瘤学;
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