Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants.
Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants.
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DOI：
10.1371/journal.pmed.0020313
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发表时间：
2005-11
期刊：
影响因子：
15.8
通讯作者：
Meyerson M
中科院分区：
文献类型：
--
作者：
Greulich H;Chen TH;Feng W;Jänne PA;Alvarez JV;Zappaterra M;Bulmer SE;Frank DA;Hahn WC;Sellers WR;Meyerson M
表皮生长因子受体酪氨酸激酶基因 EGFR 激酶结构域的体细胞突变在肺腺癌中很常见。突变的存在与肿瘤对 EGFR 抑制剂厄洛替尼和吉非替尼的敏感性相关，但特定突变的转化潜力及其与药物敏感性的关系尚未描述。在这里，我们证明 EGFR 活性位点突变体具有致癌性。在缺乏外源表皮生长因子的情况下，突变型 EGFR 可以转化成纤维细胞和肺上皮细胞，免疫功能低下小鼠的贴壁依赖性生长、病灶形成和肿瘤形成证明了这一点。转化与 EGFR 的组成型自身磷酸化、Shc 磷酸化和 STAT 通路激活相关。大多数 EGFR 突变体的转化使细胞对厄洛替尼和吉非替尼敏感，而外显子 20 插入的转化使细胞对这些抑制剂产生耐药性，但对不可逆抑制剂 CL-387,785 更敏感。不同 EGFR 突变体对细胞的致癌转化导致对吉非替尼和厄洛替尼的敏感性不同。因此，治疗含有 EGFR 外显子 20 插入的肺癌可能需要开发替代激酶抑制策略。不同的 EGFR 突变与肺癌相关。所有类别均可转化成纤维细胞和肺上皮细胞，大多数对厄洛替尼和吉非尼敏感，但外显子 20 突变仅对不可逆 EGFR 抑制剂敏感。
Somatic mutations in the kinase domain of the epidermal growth factor receptor tyrosine kinase gene EGFR are common in lung adenocarcinoma. The presence of mutations correlates with tumor sensitivity to the EGFR inhibitors erlotinib and gefitinib, but the transforming potential of specific mutations and their relationship to drug sensitivity have not been described. Here, we demonstrate that EGFR active site mutants are oncogenic. Mutant EGFR can transform both fibroblasts and lung epithelial cells in the absence of exogenous epidermal growth factor, as evidenced by anchorage-independent growth, focus formation, and tumor formation in immunocompromised mice. Transformation is associated with constitutive autophosphorylation of EGFR, Shc phosphorylation, and STAT pathway activation. Whereas transformation by most EGFR mutants confers on cells sensitivity to erlotinib and gefitinib, transformation by an exon 20 insertion makes cells resistant to these inhibitors but more sensitive to the irreversible inhibitor CL-387,785. Oncogenic transformation of cells by different EGFR mutants causes differential sensitivity to gefitinib and erlotinib. Treatment of lung cancers harboring EGFR exon 20 insertions may therefore require the development of alternative kinase inhibition strategies. Different EGFR mutations are associated with lung cancer. All of the classes can transform fibroblasts and lung epithelial cells, most are sensitive to erlotinib and gefininib, but exon 20 mutations are only sensitive to an irreversible EGFR inhibitor.