Combined Therapy with Mutant-Selective EGFR Inhibitor and Met Kinase Inhibitor for Overcoming Erlotinib Resistance in EGFR-Mutant Lung Cancer
Combined Therapy with Mutant-Selective EGFR Inhibitor and Met Kinase Inhibitor for Overcoming Erlotinib Resistance in EGFR-Mutant Lung Cancer
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DOI：
10.1158/1535-7163.mct-12-0195
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发表时间：
2012-10-01
影响因子：
5.7
通讯作者：
Yano, Seiji
中科院分区：
文献类型：
--
作者：
Nakagawa, Takayuki;Takeuchi, Shinji;Yano, Seiji
尽管EGF受体酪氨酸激酶抑制剂（EGFR-TKI）厄洛替尼和吉非替尼对EGFR突变型肺癌显示出显着疗效，但患者因多种机制产生耐药性，包括守门人EGFR-T790M突变、Met扩增和HGF过表达，随后复发。因此，迫切需要开发新药来克服 EGFR-TKI 耐药性。我们测试了突变选择性 EGFR-TKI WZ4002 和突变选择性 Met-TKI E7050 对通过不同机制对厄洛替尼耐药的 3 种 EGFR 突变型肺癌细胞系的影响：外显子 19 缺失的 PC-9/HGF 细胞、L858R 突变的 H1975 和外显子 19 缺失的 HCC827ER，由于 HGF 基因而对厄洛替尼产生耐药性分别为转染、看门人 T790M 突变和 Met 扩增。 WZ4002抑制具有看门人T790M突变的H1975细胞的生长，但不抑制HCC827ER和PC-9/HGF细胞的生长。 HGF 引发 H1975 细胞对 WZ4002 的耐药性，而 E7050 使 HCC827ER、PC-9/HGF 和 HGF 处理的 H1975 细胞对 WZ4002 敏感，抑制 EGFR 和 Met 磷酸化及其下游分子。联合治疗有效抑制了 H1975、HCC827ER 和 PC-9/HGF 细胞在严重联合免疫缺陷小鼠中诱导的肿瘤生长，且没有任何明显的不良事件。这些治疗效果与体内 EGFR 和 Met 磷酸化的抑制有关。突变选择性 EGFR-TKI 和 Met-TKI 的组合可有效抑制由守门人 T790M 突变、Met 扩增和 HGF 过表达引起的厄洛替尼耐药肿瘤的生长。临床试验中的进一步评估是必要的。摩尔癌症治疗； 11(10)； 2149-57。 (C) 2012 年 AACR。
Although the EGF receptor tyrosine kinase inhibitors (EGFR-TKI) erlotinib and gefitinib have shown dramatic effects against EGFR mutant lung cancer, patients become resistant by various mechanisms, including gatekeeper EGFR-T790M mutation, Met amplification, and HGF overexpression, thereafter relapsing. Thus, it is urgent to develop novel agents to overcome EGFR-TKI resistance. We have tested the effects of the mutant-selective EGFR-TKI WZ4002 and the mutant-selective Met-TKI E7050 on 3 EGFR mutant lung cancer cell lines resistant to erlotinib by different mechanisms: PC-9/HGF cells with an exon 19 deletion, H1975 with an L858R mutation, and HCC827ER with an exon 19 deletion, with acquired resistance to erlotinib because of HGF gene transfection, gatekeeper T790M mutation, and Met amplification, respectively. WZ4002 inhibited the growth of H1975 cells with a gatekeeper T790M mutation, but did not inhibit the growth of HCC827ER and PC-9/HGF cells. HGF triggered the resistance of H1975 cells to WZ4002, whereas E7050 sensitized HCC827ER, PC-9/HGF, and HGF-treated H1975 cells to WZ4002, inhibiting EGFR and Met phosphorylation and their downstream molecules. Combined treatment potently inhibited the growth of tumors induced in severe-combined immunodeficient mice by H1975, HCC827ER, and PC-9/HGF cells, without any marked adverse events. These therapeutic effects were associated with the inhibition of EGFR and Met phosphorylation in vivo. The combination of a mutant-selective EGFR-TKI and a Met-TKI was effective in suppressing the growth of erlotinib-resistant tumors caused by gatekeeper T790M mutation, Met amplification, and HGF overexpression. Further evaluations in clinical trials are warranted. Mol Cancer Ther; 11(10); 2149-57. (C) 2012 AACR.