Hepatocyte growth factor reduces sensitivity to the epidermal growth factor receptor-tyrosine kinase inhibitor, gefitinib, in lung adenocarcinoma cells harboring wild-type EGFR.
Hepatocyte growth factor reduces sensitivity to the epidermal growth factor receptor-tyrosine kinase inhibitor, gefitinib, in lung adenocarcinoma cells harboring wild-type EGFR.
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DOI：
10.18632/oncotarget.7586
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发表时间：
2016-03-29
期刊：
影响因子：
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通讯作者：
Wang W
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文献类型：
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作者：
Yang H;Wang R;Peng S;Chen L;Li Q;Wang W
表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）治疗是一种选择肺癌窝藏野生型EGFR时，化疗药物已经失败。在这项研究中，我们发现EGFR-TKI，吉非替尼，适度抑制肺癌细胞系A549和H358的增殖，这两种细胞系都含有野生型EGFR。用肝细胞生长因子（HGF）治疗降低了对吉非替尼的敏感性，而用HGF抗体、MET抑制剂或MET耗竭（而不是ErbB 3基因）治疗可恢复敏感性。此外，PI 3 K/mTOR抑制剂和MEK抑制剂均抑制A549细胞的增殖，而仅PI 3 K/mTOR抑制剂有效抑制EGFR突变PC-9细胞的细胞活力。我们的研究结果表明，HGF通过MET和下游PI 3 K和MAPK途径降低吉非替尼的敏感性。EGFR-TKI和MET抑制剂联合使用或抑制下游信号分子可能是一组携带野生型EGFR的晚期肺癌患者更好的二线或三线选择。
Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy is an option for lung cancers harboring wild-type EGFR when chemotherapeutic reagents have failed. In this study, we found that the EGFR-TKI, gefitinib, modestly suppressed proliferation of the lung cancer cell lines, A549 and H358, which both harbor wild-type EGFR. Treatment with hepatocyte growth factor (HGF) reduced the sensitivity to gefitinib, whereas sensitivity was restored by treatment with an HGF antibody, a MET inhibitor, or depletion of MET but not ErbB3 gene. Moreover, both PI3K/mTOR inhibitors and MEK inhibitors suppressed proliferation of A549 cells, whereas only PI3K/mTOR inhibitors effectively suppressed cell viability of EGFR mutant PC-9 cells. Our findings suggest that HGF reduced the gefitinib sensitivity through MET and downstream PI3K and MAPK pathways. Combined use of EGFR-TKI and MET inhibitors or inhibition of downstream signaling molecules might be a better second or third line choice for a group of patients with advanced lung cancer harboring wild-type EGFR.