Dual Inhibition of Met Kinase and Angiogenesis to Overcome HGF-Induced EGFR-TKI Resistance in EGFR Mutant Lung Cancer
Dual Inhibition of Met Kinase and Angiogenesis to Overcome HGF-Induced EGFR-TKI Resistance in EGFR Mutant Lung Cancer
复制标题
双重抑制 Met 激酶和血管生成，以克服 EGFR 突变型肺癌中 HGF 诱导的 EGFR-TKI 耐药性。
DOI：
10.1016/j.ajpath.2012.05.023
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发表时间：
2012-09-01
影响因子：
6
通讯作者：
Yano, Seiji
中科院分区：
文献类型：
--
作者：
Takeuchi, Shinji;Wang, Wei;Yano, Seiji
对表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）的获得性耐药是EGFR突变型肺癌治疗中的一个严重问题。我们最近报道肝细胞生长因子（HGF）通过激活Met/PI 3 K通路诱导对EGFR-TKI的耐药性。HGF还已知与血管内皮生长因子（VEGF）协同诱导血管生成，其是肺癌的重要治疗靶点。因此，我们假设HGF和VEGF的双重抑制可能在治疗上用于控制HGF诱导的EGFR-TKI抗性肺癌。我们发现，一个双重的Met/VEGF受体2激酶抑制剂，E7050，规避HGF诱导的EGFR突变型肺癌细胞系的EGFR-TKI耐药通过抑制Met/Gab 1/PI 3 K/Akt途径在体外。HGF通过激活EGFR突变肺癌细胞系中的Met/Gab 1信号通路刺激VEGF的产生，E7050显示出抑制作用。在异种移植模型中，由HGF转染的Ma-1（Ma-1/HGF）细胞产生的肿瘤比载体对照肿瘤更具血管生成性，并显示出对吉非替尼的耐药性。E7050单独抑制Ma-1/HGF肿瘤的血管生成和延迟生长。E7050联合吉非替尼诱导肿瘤生长显著消退。此外，通过中和抗体与吉非替尼组合的HGF和VEGF的双重抑制也显著地使肿瘤生长消退。这些结果表明，双重靶向HGF-Met和VEGF VEGF受体2用于克服EGFR突变型肺癌中HGF诱导的EGFR-TKI抗性的治疗原理。(Am J Pathol 2012，181：1034-1043; http：//dx.doi.org/10.1016/j.ajpath.2012.05.023）
Acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is a serious problem in the management of EGFR mutant lung cancer. We recently reported that hepatocyte growth factor (HGF) induces resistance to EGFR-TKIs by activating the Met/PI3K pathway. HGF is also known to induce angiogenesis in cooperation with vascular endothelial growth factor (VEGF), which is an important therapeutic target in lung cancer. Therefore, we hypothesized that dual inhibition of HGF and VEGF may be therapeutically useful for controlling HGF-induced EGFR-TKI resistant lung cancer. We found that a dual Met/VEGF receptor 2 kinase inhibitor, E7050, circumvented HGF-induced EGFR-TKI resistance in EGFR mutant lung cancer cell lines by inhibiting the Met/Gab1/PI3K/Akt pathway in vitro. HGF stimulated VEGF production by activation of the Met/Gab1 signaling pathway in EGFR mutant lung cancer cell lines, and E7050 showed an inhibitory effect. In a xenograft model, tumors produced by HGF-transfected Ma-1 (Ma-1/HGF) cells were more angiogenic than vector control tumors and showed resistance to gefitinib. E7050 alone inhibited angiogenesis and retarded growth of Ma-1/HGF tumors. E7050 combined with gefitinib induced marked regression of tumor growth. Moreover, dual inhibition of HGF and VEGF by neutralizing antibodies combined with gefitinib also markedly regressed tumor growth. These results indicate the therapeutic rationale of dual targeting of HGF-Met and VEGF VEGF receptor 2 for overcoming HGF-induced EGFR-TKI resistance in EGFR mutant lung cancer. (Am J Pathol 2012,181:1034-1043; http://dx.doi.org/10.1016/j.ajpath.2012.05.023)