Epidermal growth factor receptor variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase inhibitors
Epidermal growth factor receptor variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase inhibitors
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DOI：
10.1073/pnas.0510284103
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发表时间：
2006-05-16
影响因子：
11.1
通讯作者：
Wong, Kwok-Kin
中科院分区：
文献类型：
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作者：
Ji, Hongbin;Zhao, Xiaojun;Wong, Kwok-Kin
酪氨酸激酶抑制剂吉非替尼（易瑞沙）和厄洛替尼（特罗凯）在非小细胞肺癌（NSCLC）的治疗中显示出抗肿瘤活性。在表皮生长因子受体（EGFR）酪氨酸激酶结构域发生突变的非小细胞肺癌肿瘤中，出现了显著且持久的疗效。相比之下，这些抑制剂在胶质母细胞瘤中的疗效有限，在胶质母细胞瘤中通常发现一种独特的EGFR突变，即外显子2 - 7的变异III（vIII）框内缺失。在这项研究中，我们确定在所分析的人类肺鳞状细胞癌（SCC）中有5%（3/56）存在EGFRvIII突变，而在人类肺腺癌中未发现（0/123）。我们分析了EGFRvIII突变在肺肿瘤发生中的作用及其对酪氨酸激酶抑制的反应。EGFRvIII在小鼠肺中的组织特异性表达导致了非小细胞肺癌的发生。最重要的是，这些肺肿瘤的维持依赖于EGFRvIII的表达。用一种不可逆的EGFR抑制剂HKI - 272治疗，在1周内显著减小了这些由EGFRvIII驱动的小鼠肿瘤的大小。同样，用EGFRvIII突变体转化的Ba/F3细胞在体外对吉非替尼和厄洛替尼相对耐药，但对HKI - 272敏感。这些发现为携带EGFRvIII突变的癌症提出了一种治疗策略。
The tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva) have shown anti-tumor activity in the treatment of non-small cell lung cancer (NSCLC). Dramatic and durable responses have occurred in NSCLC tumors with mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). In contrast, these inhibitors have shown limited efficacy in glioblastoma, where a distinct EGFR mutation, the variant III (vIII) in-frame deletion of exons 2-7, is commonly found. In this study, we determined that EGFRvIII mutation was present in 5% (3/56) of analyzed human lung squamous cell carcinoma (SCC) but was not present in human lung adenocarcinoma (0/123). We analyzed the role of the EGFRvIII mutation in lung tumorigenesis and its response to tyrosine kinase inhibition. Tissue-specific expression of EGFRvIII in the murine lung led to the development of NSCLC. Most importantly, these lung tumors depend on EGFRvIII expression for maintenance. Treatment with an irreversible EGFR inhibitor, HKI-272, dramatically reduced the size of these EGFRvIII-driven murine tumors in 1 week. Similarly, Ba/F3 cells transformed with the EGFRvIII mutant were relatively resistant to gefitinib and erlotinib in vitro but proved sensitive to HKI-272. These findings suggest a therapeutic strategy for cancers harboring the EGFRvIII mutation.