Crizotinib overcomes hepatocyte growth factor-mediated resistance to gefitinib in EGFR-mutant non-small-cell lung cancer cells
Crizotinib overcomes hepatocyte growth factor-mediated resistance to gefitinib in EGFR-mutant non-small-cell lung cancer cells
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克唑替尼克服了 EGFR 突变非小细胞肺癌细胞中肝细胞生长因子介导的吉非替尼耐药性
DOI：
10.1097/cad.0000000000000011
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发表时间：
2013-11-01
影响因子：
2.3
通讯作者：
Zhou, Jian-Ying
中科院分区：
文献类型：
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作者：
Chen, Xi;Zhou, Jian-Ya;Zhou, Jian-Ying
获得性耐药最终在大多数表皮生长因子受体（EGFR）突变的非小细胞肺癌患者中发展，这些患者最初对EGFR酪氨酸激酶抑制剂有反应。肝细胞生长因子（HGF）的过度表达是获得性耐药的重要原因。因此，需要新的方法来更好地管理以克服耐药性。在这里，我们测试了克唑替尼（PF 02341066），一种MET激酶抑制剂，是否可以克服人类EGFR突变肺癌细胞系HCC 827和PC-9中两种不同的HGF触发的吉非替尼耐药机制。与单药治疗相比，克唑替尼和吉非替尼联合治疗通过阻断MET/PI 3 K/Akt通路诱导细胞凋亡并显著抑制HGF存在下的细胞生长。此外，我们证明了克唑替尼联合吉非替尼成功地阻止了短暂暴露于HGF诱导的吉非替尼耐药HCC 827细胞的出现。在体内，克唑替尼和吉非替尼联合治疗也显著抑制了吉非替尼耐药小鼠异种移植物的生长，该异种移植物是通过将混合有HGF产生成纤维细胞（MRC-5细胞）的HCC 827细胞皮下注射到重度联合免疫缺陷小鼠中建立的。总之，这些发现提供了临床前证据，证明克唑替尼可用于治疗EGFR突变型肺癌中HGF诱导的吉非替尼耐药。
Acquired resistance develops ultimately in most non-small-cell lung cancer patients with epidermal growth factor receptor (EGFR) mutations who initially respond to EGFR tyrosine kinase inhibitors. Overexpression of hepatocyte growth factor (HGF) contributes to a considerable part of acquired resistance. Therefore, novel approaches are required for better management to overcome the resistance. Here, we tested whether crizotinib (PF02341066), a MET kinase inhibitor, can overcome two different HGF-triggered mechanisms of resistance to gefitinib in human EGFR mutant lung cancer cell lines HCC827 and PC-9. Compared with the monotherapy, the combined treatment of crizotinib and gefitinib induced apoptosis and significantly inhibited the growth of cells in the presence of HGF by blocking the MET/PI3K/Akt pathway. Further, we demonstrated that crizotinib plus gefitinib successfully prevented the emergence of gefitinib-resistant HCC827 cells induced by transient exposure to HGF. In vivo, the combination therapy with crizotinib and gefitinib also markedly suppressed the growth of gefitinib-resistant mouse xenografts established by injecting HCC827 cells mixed with HGF-producing fibroblasts (MRC-5 cells) subcutaneously into severe combined immunodeficient mice. In conclusion, these findings provided preclinical evidence that crizotinib can be used in the treatment of HGF-induced resistance to gefitinib in EGFR mutant lung cancer.