Reciprocal and Complementary Role of MET Amplification and EGFR T790M Mutation in Acquired Resistance to Kinase Inhibitors in Lung Cancer
Reciprocal and Complementary Role of MET Amplification and EGFR T790M Mutation in Acquired Resistance to Kinase Inhibitors in Lung Cancer
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DOI：
10.1158/1078-0432.ccr-10-1371
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发表时间：
2010-11-15
影响因子：
11.5
通讯作者：
Mitsudomi, Tetsuya
中科院分区：
文献类型：
--
作者：
Suda, Kenichi;Murakami, Isao;Mitsudomi, Tetsuya
目的：在肺癌患者的表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）治疗中，几乎不可避免地产生获得性耐药，这限制了患者结局的改善。EGFR T790 M突变和MET扩增是导致这种耐药的两种主要机制，但这两种机制之间的关系尚不清楚。在这项研究中，我们探讨了它们之间的关系，在体外模型和尸检samples.Experimental设计：厄洛替尼耐药HCC 827（HCC 827 ER）细胞的开发，通过慢性暴露于厄洛替尼在不断增加的浓度。在PHA-665，752（一种MET TKI）存在下，通过长期暴露于厄洛替尼也可培养HCC 827 EPR细胞。分析这些细胞的厄洛替尼耐药机制。结果：HCC 827 ER发生MET扩增，临床相关耐药发生在MET基因拷贝数增加>= 4倍（CNG）时。相比之下，HCC 827 EPR开发了没有MET CNG的T790 M。在6名患有吉非替尼难治性肿瘤的患者中，3名仅表现出T790 M，1名仅表现出MET扩增，另外2名表现出T790 M和/或MET扩增，这取决于病变部位。在这些吉非替尼难治性肿瘤中，93%（14/15）的无MET基因CNG肿瘤、80%（4/5）的中度MET基因CNG肿瘤（
Purpose: In epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy for lung cancer patients, acquired resistance develops almost inevitably and this limits the improvement in patient outcomes. EGFR T790M mutation and MET amplification are the two main mechanisms underlying this resistance, but the relationship between these two mechanisms is unclear. In this study, we explored their relationship using in vitro models and autopsy specimens.Experimental Design: Erlotinib-resistant HCC827 (HCC827ER) cells were developed by chronic exposure to erlotinib at increasing concentrations. HCC827EPR cells were also developed by chronic exposure to erlotinib in the presence of PHA-665,752 (a MET TKI). The erlotinib-resistant mechanisms of these cells were analyzed. In addition, 33 autopsy tumor samples from 6 lung adenocarcinoma patients harboring multiple gefitinib- refractory tumors were analyzed.Results: HCC827ER developed MET amplification, and clinically relevant resistance occurred at >= 4-fold MET gene copy number gain (CNG). By contrast, HCC827EPR developed T790M without MET CNG. Of six patients harboring gefitinib- refractory tumors, three exhibited T790M only, one exhibited MET amplification only, and the other two exhibited T790M and/or MET amplification depending on the lesion sites. In these gefitinib- refractory tumors, T790M developed in 93% (14 of 15) of tumors without MET gene CNGs, in 80% (4 of 5) of tumors with moderate MET gene CNGs (