Epidermal growth factor receptor variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase inhibitors

作者：Hongbin Ji, Xiaojun Zhao, Yuki Yuza, Takeshi Shimamura, Danan Li, Alexei I. Protopopov, Boonim L. Jung, Kate L. McNamara, Huili Xia, Karen A. Glatt, Roman Kurt Thomas, Hidefumi Sasaki, James W. Horner, Michael J. Eck, Mitchell Albert, Yangping Sun, Ruqayyah Al-Hashem, Roderick Terry Bronson, Sridhar K. Rabindran, Carolyn M. Discafani, Elizabeth Anne Maher, Geoffrey Ira Shapiro, Matthew M. Meyerson, Kwok‐Kin Wong · 发表于：Proceedings of the National Academy of Sciences · 年份：2006 · DOI：10.1073/pnas.0510284103 · 被引用次数：259 · 研究领域：Lung Cancer Treatments and Mutations、HER2/EGFR in Cancer Research、Gastric Cancer Management and Outcomes

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.