Hepatocyte Growth Factor Induces Gefitinib Resistance of Lung Adenocarcinoma with Epidermal Growth Factor Receptor-Activating Mutations
Hepatocyte Growth Factor Induces Gefitinib Resistance of Lung Adenocarcinoma with Epidermal Growth Factor Receptor-Activating Mutations
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DOI：
10.1158/0008-5472.can-08-1643
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发表时间：
2008-11-15
期刊：
影响因子：
11.2
通讯作者：
Sone, Saburo
中科院分区：
文献类型：
--
作者：
Yano, Seiji;Wang, Wei;Sone, Saburo
表皮生长因子受体（EGFR）激活突变的肺癌对EGFR酪氨酸激酶抑制剂吉非替尼和厄洛替尼的反应良好。然而，25%至30%的EGFR激活突变患者表现出内在耐药性，并且应答者总是获得对吉非替尼的耐药性。在这里，我们发现肝细胞生长因子（HGF），MET癌蛋白的配体，诱导吉非替尼耐药的肺腺癌细胞与EGFR激活突变恢复磷脂酰肌醇3-激酶/Akt信号通路通过磷酸化MET，但不是EGFR或ErbB 3。在携带EGFR激活突变的肺腺癌患者中检测到癌细胞中HGF的强免疫反应性，但没有T790 M突变或MET扩增，这些患者对吉非替尼表现出内在或获得性耐药。研究结果表明，HGF介导的MET激活是EGFR激活突变肺腺癌吉非替尼耐药的一种新机制。因此，抑制HGF-MET信号传导可能是吉非替尼更成功治疗的重要策略。[Cancer Res 2008;68（22）：9479-87]
Lung cancer with epidermal growth factor receptor (EGFR)activating mutations responds favorably to the EGFR tyrosine kinase inhibitors gefitinib and erlotinib. However, 25% to 30% of patients with EGFR-activating mutations show intrinsic resistance, and the responders invariably acquire resistance to gefitinib. Here, we showed that hepatocyte growth factor (HGF), a ligand of MET oncoprotein, induces gefitinib resistance of lung adenocarcinoma cells with EGFR-activating mutations by restoring the phosphatidylinositol 3-kinase/Akt signaling pathway via phosphorylation of MET, but not EGFR or ErbB3. Strong immunoreactivity for HGF in cancer cells was detected in lung adenocarcinoma patients harboring EGFR-activating mutations, but no T790M mutation or MET amplification, who showed intrinsic or acquired resistance to gefitinib. The findings indicate that HGF-mediated MET activation is a novel mechanism of gefitinib resistance in lung adenocarcinoma with EGFR-activating mutations. Therefore, inhibition of HGF-MET signaling may be a considerable strategy for more successful treatment with gefitinib. [Cancer Res 2008;68(22):9479-87]