Hepatocyte Growth Factor Induces Resistance to Anti-Epidermal Growth Factor Receptor Antibody in Lung Cancer
Hepatocyte Growth Factor Induces Resistance to Anti-Epidermal Growth Factor Receptor Antibody in Lung Cancer
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DOI：
10.1097/jto.0b013e3182398e69
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发表时间：
2012-02-01
影响因子：
20.4
通讯作者：
Yano, Seiji
中科院分区：
文献类型：
--
作者：
Yamada, Tadaaki;Takeuchi, Shinji;Yano, Seiji
表皮生长因子受体（EGFR）是肺癌治疗中一个有吸引力的药物靶点，几种抗EGFR抗体和小分子抑制剂在肺癌患者中显示出疗效。然而，患者可能对EGFR抑制剂产生耐药性。我们以前证明，肝细胞生长因子（HGF）诱导耐药EGFR酪氨酸激酶抑制剂在肺癌窝藏EGFR突变。因此，我们确定了HGF是否可以诱导肺癌细胞对抗EGFR抗体（EGFR Ab）西妥昔单抗的耐药性，无论EGFR基因状态如何。研究方法：在存在或不存在HGF、产生HGF的成纤维细胞和用HGF基因转染的细胞的情况下，在体外和体内检查肺癌细胞中的西妥昔单抗敏感性和信号转导。结果：HGF诱导H292（EGFR野生型）和Ma-1（EGFR突变型）细胞对西妥昔单抗产生耐药性。Western blotting结果显示HGF诱导的抗性是通过Met/Gab1/Akt信号通路介导的。H292和Ma-1细胞对西妥昔单抗的抗性也通过与产生高水平HGF的肺成纤维细胞共培养和通过稳定转染HGF基因的细胞诱导。通过用抗HGF中和抗体治疗消除这种抗性。结论：HGF介导的耐药是肺癌对EGFR Ab耐药的一种新机制，成纤维细胞来源的HGF在体内诱导H292肿瘤对西妥昔单抗耐药。无论EGFR基因状态如何，均应评估HGF-Met介导的信号传导参与肺癌EGFR Ab获得性耐药的情况。
Epidermal growth factor receptor (EGFR) is an attractive drug target in lung cancer, with several anti-EGFR antibodies and small-molecule inhibitors showing efficacy in lung cancer patients. Patients, however, may develop resistance to EGFR inhibitors. We demonstrated previously that hepatocyte growth factor (HGF) induced resistance to EGFR tyrosine kinase inhibitors in lung cancers harboring EGFR mutations. We therefore determined whether HGF could induce resistance to the anti-EGFR antibody (EGFR Ab) cetuximab in lung cancer cells, regardless of EGFR gene status. Methods: Cetuximab sensitivity and signal transduction in lung cancer cells were examined in the presence or absence of HGF, HGF-producing fibroblasts, and cells tranfected with the HGF gene in vitro and in vivo. Results: HGF induced resistance to cetuximab in H292 (EGFR wild) and Ma-1(EGFR mutant) cells. Western blotting showed that HGF-induced resistance was mediated by the Met/Gab1/Akt signaling pathway. Resistance of H292 and Ma-1 cells to cetuximab was also induced by coculture with lung fibroblasts producing high levels of HGF and by cells stably transfected with the HGF gene. This resistance was abrogated by treatment with anti-HGF neutralizing antibody. Conclusions: HGF-mediated resistance is a novel mechanism of resistance to EGFR Ab in lung cancers, with fibroblast-derived HGF inducing cetuximab resistance in H292 tumors in vivo. The involvement of HGF-Met-mediated signaling should be assessed in acquired resistance to EGFR Ab in lung cancer, regardless of EGFR gene status.