Hepatocyte Growth Factor Reduces Susceptibility to an Irreversible Epidermal Growth Factor Receptor Inhibitor in EGFR-T790M Mutant Lung Cancer
Hepatocyte Growth Factor Reduces Susceptibility to an Irreversible Epidermal Growth Factor Receptor Inhibitor in EGFR-T790M Mutant Lung Cancer
复制标题
DOI：
10.1158/1078-0432.ccr-09-1204
复制
发表时间：
2010-01-01
影响因子：
11.5
通讯作者：
Yano, Seiji
中科院分区：
文献类型：
--
作者：
Yamada, Tadaaki;Matsumoto, Kunio;Yano, Seiji
目的：表皮生长因子受体（EGFR）的继发性T790 M突变是肺癌中对可逆性EGFR酪氨酸激酶抑制剂（EGFR-TKI）吉非替尼和厄洛替尼获得性耐药的最常见原因。不可逆的EGFR-TKI有望克服EGFR中携带T790 M突变的肺癌的可逆EGFR-TKI耐药性。然而，很明显，耐药性也可能对这类抑制剂产生。我们以前的研究表明，肝细胞生长因子（HGF）诱导的肺癌吉非替尼耐药性携带EGFR激活突变。在此，我们研究了HGF是否在携带EGFR中的L 858 R激活突变和T790 M继发突变的肺癌细胞（H1975）中诱导对不可逆EGFR-TKI CL-387，785的抗性。CL-387，785敏感性和H1975细胞中的信号转导在存在或不存在HGF或具有或不具有HGF-785的产生HGF的成纤维细胞的情况下进行检查。MET抑制剂。结果：HGF降低了H1975细胞对CL-387，785的敏感性。Western blotting和小分子干扰RNA分析表明，HGF诱导的低敏感性是由MET/磷酸肌醇3-激酶/Akt信号通路介导的，不依赖于EGFR、ErbB 2、ErbB 3和ErbB 4。H1975细胞对CL-387，785的低敏感性也通过与高水平的产生HGF的肺成纤维细胞共培养诱导。通过抗HGF中和抗体、HGF拮抗剂NK 4或MET-TKI.Conclusions治疗，可消除敏感性降低。研究HGF-MET介导的信号通路参与EGFR T790 M突变肺癌对EGFR-TKI的原发性和获得性不可逆耐药具有重要的临床价值。临床癌症研究; 16（1）; 174-83。（C）2010年AACR。
Purpose: The secondary T790M mutation in epidermal growth factor receptor (EGFR) is the most frequent cause of acquired resistance to the reversible EGFR tyrosine kinase inhibitors (EGFR-TKI), gefitinib and erlotinib, in lung cancer. Irreversible EGFR-TKIs are expected to overcome the reversible EGFR-TKI resistance of lung cancer harboring T790M mutation in EGFR. However, it is clear that resistance may also develop to this class of inhibitors. We showed previously that hepatocyte growth factor (HGF) induced gefitinib resistance of lung cancer harboring EGFR-activating mutations. Here, we investigated whether HGF induced resistance to the irreversible EGFR-TKI, CL-387,785, in lung cancer cells (H1975) harboring both L858R activating mutation and T790M secondary mutation in EGFR.Experimental Design: CL-387,785 sensitivity and signal transduction in H1975 cells were examined in the presence or absence of HGF or HGF-producing fibroblasts with or without HGF-MET inhibitors.Results: HGF reduced susceptibility to CL-387,785 in H1975 cells. Western blotting and small interfering RNA analyses indicated that HGF-induced hyposensitivity was mediated by the MET/ phosphoinositide 3-kinase/Akt signaling pathway independent of EGFR, ErbB2, ErbB3, and ErbB4. Hyposensitivity of H1975 cells to CL-387,785 was also induced by coculture with high-level HGF-producing lung fibroblasts. The hyposensitivity was abrogated by treatment with anti-HGF neutralizing antibody, HGF antagonist NK4, or MET-TKI.Conclusions: We showed HGF-mediated hyposensitivity as a novel mechanism of resistance to irreversible EGFR-TKIs. It will be clinically valuable to investigate the involvement of HGF-MET-mediated signaling in de novo and acquired resistance to irreversible EGFR-TKIs in lung cancer harboring T790M mutation in EGFR. Clin Cancer Res; 16(1); 174-83. (C)2010 AACR.