Co-Activation of Epidermal Growth Factor Receptor and c-MET Defines a Distinct Subset of Lung Adenocarcinomas
Co-Activation of Epidermal Growth Factor Receptor and c-MET Defines a Distinct Subset of Lung Adenocarcinomas
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DOI：
10.2353/ajpath.2010.100217
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发表时间：
2010-11-01
影响因子：
6
通讯作者：
Niki, Toshiro
中科院分区：
文献类型：
--
作者：
Matsubara, Daisuke;Ishikawa, Shumpei;Niki, Toshiro
表皮生长因子受体(EGFR)和MET是肺癌治疗的分子靶点。这两个靶点的表达、激活和基因异常之间的关系目前尚不清楚。在这里，我们展示了一个由40个肺癌细胞株组成的小组可以分为两组。I组的特征是：(1)MET和EGFR的高磷酸化；(2)EGFR、MET和人表皮生长因子受体-2(HER2)的频繁突变或扩增；(3)支气管上皮标志物(甲状腺转录因子-1(TTF-1)、MUG！和细胞角蛋白7(CK7))的高表达；(4)MET、人表皮生长因子受体-3、E-钙粘素、环氧合酶-2和层粘连蛋白的高表达。与之相反，第11组MET和EGFR的磷酸化程度很低或没有；EGFR、MET和HER2没有突变或扩增；TTF-1、MUC1和CK7呈三重阴性；Vimentin、成纤维细胞生长因子受体-1和转录因子8高表达。重要的是，I组比II组对吉非替尼更敏感，对顺铂和紫杉醇的耐药性更强。术后化疗的生存益处仅见于与II组对应的肿瘤患者。总体而言，EGFR和MET的共同激活定义了一个独特的肺癌亚组，具有典型的遗传异常、基因表达模式和对化疗药物的反应。(Am J Pathol 2010,177：2191-2204 DOI：10.2353/ajpath.2010.100217)
Epidermal growth factor receptor (EGFR) and MET are molecular targets for lung cancer treatment. The relationships between expression, activation, and gene abnormalities of these two targets are currently unclear. Here, we demonstrate that a panel of 40 lung cancer cell lines could be classified into two groups. Group I was characterized by (1) high phosphorylations of MET and EGFR, (2) frequent mutation or amplification of EGFR, MET, and human epidermal growth factor receptor-2 (HER2), (3) high expressions of bronchial epithelial markers (thyroid transcription factor-1 (TTF-1), MUG!, and Cytokeratin 7 (CK7)); and (4) high expressions of MET, human epidermal growth factor receptor-3, E-cadherin, cyclooxygenase-2, and laminin gamma2. In contrast, Group 11 exhibited little or no phosphorylation of MET and EGFR; no mutation or amplification of EGFR, MET, and HER2; were triple-negative for TTF-1, MUC1, and CK7; and showed high expressions of vimentin, fibroblast growth factor receptor-1, and transcription factor 8. Importantly, Group I was more sensitive to gefitinib and more resistant to cisplatin and paclitaxel than Group II. The clinical relevance was confirmed in publicly available data on 442 primary lung adenocarcinoma patients; survival benefits by postoperative chemotherapy were seen in only patients with tumors corresponding to Group II. Overall, co-activation of EGFR and MET defines a distinct subgroup of lung carcinoma with characteristic genetic abnormalities, gene expression pattern, and response to chemotherapeutic reagents. (Am J Pathol 2010, 177:2191-2204 DOI: 10.2353/ajpath.2010.100217)