Novel MEK1 mutation identified by mutational analysis of epidermal growth factor receptor signaling pathway genes in lung adenocarcinoma.
Novel MEK1 mutation identified by mutational analysis of epidermal growth factor receptor signaling pathway genes in lung adenocarcinoma.
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DOI：
10.1158/0008-5472.can-08-0099
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发表时间：
2008-07-15
期刊：
影响因子：
11.2
通讯作者：
Pao, William
中科院分区：
文献类型：
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作者：
Marks, Jenifer L.;Gong, Yixuan;Chitale, Dhananjay;Golas, Ben;McLellan, Michael D.;Kasai, Yumi;Ding, Li;Mardis, Elaine R.;Wilson, Richard K.;Solit, David;Levine, Ross;Michel, Kathrin;Thomas, Roman K.;Rusch, Valerie W.;Ladanyi, Marc;Pao, William
影响表皮生长因子受体（EGFR）信号通路内的许多激酶和其他元件的遗传病变与人类非小细胞肺癌（NSCLC）的发病机制有关。我们对一个大的肺腺癌队列进行了突变分析，以揭示该途径基因中可能导致肺肿瘤发生的其他潜在体细胞突变。我们已经在207例原发性肺肿瘤中的2例中鉴定了MEK 1外显子2的体细胞激活突变（即，丝裂原活化蛋白激酶激酶1或MAP 2K 1），其在激酶的非激酶部分的氨基酸57（K57 N）处用天冬酰胺取代赖氨酸。这两种肿瘤都没有在编码EGFR信号传导途径组分的其他基因中携带已知的突变（即，EGFR、HER2、KRAS、PIK3CA和BRAF）。突变体而非野生型MEK 1的表达导致人293 T细胞中细胞外信号调节激酶（ERK）-1/2的组成性活性和鼠Ba/F3细胞的生长因子非依赖性增殖。选择性MEK抑制剂AZD 6244可抑制293 T细胞中MUR诱导的ERK活性和携带MUR的Ba/F3细胞的生长。我们还筛选了85个NSCLC细胞系的MEK 1外显子2突变;一个细胞系（NCI-H1437）含有Q56 P置换，这是一种最初在大鼠成纤维细胞中发现的已知的MEK 1转化能力等位基因，对AZD 6244治疗敏感。MEK 1突变体以前没有在肺癌中报道过，可能为一小部分肺腺癌患者提供有效治疗的靶点。
Genetic lesions affecting a number of kinases and other elements within the epidermal growth factor receptor (EGFR) signaling pathway have been implicated in the pathogenesis of human non–small-cell lung cancer (NSCLC). We performed mutational profiling of a large cohort of lung adenocarcinomas to uncover other potential somatic mutations in genes of this pathway that could contribute to lung tumorigenesis. We have identified in 2 of 207 primary lung tumors a somatic activating mutation in exon 2 of MEK1 (i.e., mitogen-activated protein kinase kinase 1 or MAP2K1) that substitutes asparagine for lysine at amino acid 57 (K57N) in the nonkinase portion of the kinase. Neither of these two tumors harbored known mutations in other genes encoding components of the EGFR signaling pathway (i.e., EGFR, HER2, KRAS, PIK3CA, and BRAF). Expression of mutant, but not wild-type, MEK1 leads to constitutive activity of extracellular signal–regulated kinase (ERK)-1/2 in human 293T cells and to growth factor–independent proliferation of murine Ba/F3 cells. A selective MEK inhibitor, AZD6244, inhibits mutant-induced ERK activity in 293T cells and growth of mutant-bearing Ba/F3 cells. We also screened 85 NSCLC cell lines for MEK1 exon 2 mutations; one line (NCI-H1437) harbors a Q56P substitution, a known transformation-competent allele of MEK1 originally identified in rat fibroblasts, and is sensitive to treatment with AZD6244. MEK1 mutants have not previously been reported in lung cancer and may provide a target for effective therapy in a small subset of patients with lung adenocarcinoma.