Differential constitutive activation of the epidermal growth factor receptor in non-small cell lung cancer cells bearing EGFR gene mutation and amplification
Differential constitutive activation of the epidermal growth factor receptor in non-small cell lung cancer cells bearing EGFR gene mutation and amplification
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DOI：
10.1158/0008-5472.can-06-3339
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发表时间：
2007-03-01
期刊：
影响因子：
11.2
通讯作者：
Nakagawa, Kazuhiko
中科院分区：
文献类型：
--
作者：
Okabe, Takafumi;Okamoto, Isamu;Nakagawa, Kazuhiko
非小细胞肺癌 (NSCLC) 患者表皮生长因子受体 (EGFR) 酪氨酸激酶结构域体细胞突变的鉴定以及此类突变与 EGFR 酪氨酸激酶抑制剂 (TKI)（如吉非替尼和厄洛替尼）临床反应的关联，对该疾病的治疗产生了重大影响。 EGFR 基因扩增也与 EGFR-TKI 治疗反应的增强有关。然而，这两种类型的 EGFR 改变对 EGFR 功能的影响仍不清楚。我们现在已经检查了 16 个 NSCLC 细胞系，包括来自日本 NSCLC 患者的 8 个新建立的细胞系，以确定是否存在 EGFR 突变和扩增。 6 个携带 EGFR 突变的细胞系中有 4 个被发现对 EGFR 扩增呈阳性，而 10 个 EGFR 突变阴性的细胞系中没有一个表现出 EGFR 扩增，表明这两种类型的 EGFR 改变密切相关。 EGFR 突变和扩增均呈阳性的 NSCLC 细胞系中表达的内源 EGFR 被发现由于配体非依赖性二聚化而被组成型激活。此外，在携带两种最常见的 EGFR 突变类型（外显子 19 缺失和外显子 21 中的 L858R 点突变）的细胞系之间，EGFR 扩增和 EGFR 自磷酸化的模式显示出差异。这些结果揭示了 NSCLC 细胞系中表达的 EGFR 内源突变形式的独特生化特性，并可能对这种疾病的治疗产生影响。
The identification of somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) in patients with non-small cell lung cancer (NSCLC) and the association of such mutations with the clinical response to EGFR tyrosine kinase inhibitors (TKI), such as gefitinib and erlotinib, have had a substantial effect on the treatment of this disease. EGFR gene amplification has also been associated with an increased therapeutic response to EGFR-TKIs. The effects of these two types of EGFR alteration on EGFR function have remained unclear, however. We have now examined 16 NSCLC cell lines, including eight newly established lines from Japanese NSCLC patients, for the presence of EGFR mutations and amplification. Four of the six cell lines that harbor EGFR mutations were found to be positive for EGFR amplification, whereas none of the 10 cell lines negative for EGFR mutation manifested EGFR amplification, suggesting that these two types of EGFR alteration are closely associated. Endogenous EGFRs expressed in NSCLC cell lines positive for both EGFR mutation and amplification were found to be constitutively activated as a result of ligand-independent dimerization. Furthermore, the patterns of both EGFR amplification and EGFR autophosphorylation were shown to differ between cell lines harboring the two most common types of EGFR mutation (exon 19 deletion and L858R point mutation in exon 21). These results reveal distinct biochemical properties of endogenous mutant forms of EGFR expressed in NSCLC cell lines and may have implications for treatment of this condition.