Ji Hongbin, Zhao Xiaojun, Yuza Yuki, Shimamura Takeshi, Li Danan, Protopopov Alexei, Jung Boonim L, McNamara Kate, Xia Huili, Glatt Karen A, Thomas Roman K, Sasaki Hidefumi, Horner James W, Eck Michael, Mitchell Albert, Sun Yangping, Al-Hashem Ruqayyah, Bronson Roderick T, Rabindran Sridhar K, Discafani Carolyn M, Maher Elizabeth, Shapiro Geoffrey I, Meyerson Matthew, Wong Kwok-Kin
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2006 May 16;103(20):7817-22. doi: 10.1073/pnas.0510284103. Epub 2006 May 3.
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.
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）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NSCLC肿瘤中出现了显著且持久的反应。相比之下，这些抑制剂在胶质母细胞瘤中疗效有限，胶质母细胞瘤中常见一种独特的EGFR突变，即外显子2 - 7的III型（vIII）框内缺失。在本研究中，我们确定EGFRvIII突变存在于5%（3/56）的分析人类肺鳞状细胞癌（SCC）中，但在人类肺腺癌中不存在（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NSCLC的发生。最重要的是，这些肺肿瘤依赖于EGFRvIII的表达来维持。用不可逆的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。这些发现提示了一种针对携带EGFRvIII突变癌症的治疗策略。
