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

Hongbin Ji, Xiaojun Zhao, Yuki Yuza, Takeshi Shimamura, Danan Li, Alexei Protopopov, Boonim L. Jung, Kate McNamara, Huili Xia, Karen A. Glatt, Roman K. Thomas, Hidefumi Sasaki, James W. Horner, Michael Eck, Albert Mitchell, Yangping Sun, Ruqayyah Al-Hashem, Roderick T. Bronson, Sridhar K. Rabindran, Carolyn M. DiscafaniElizabeth Maher, Geoffrey I. Shapiro, Matthew Meyerson, Kwok Kin Wong

Research output: Contribution to journalArticle

212 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)7817-7822
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number20
DOIs
Publication statusPublished - May 16 2006

    Fingerprint

Keywords

  • Irreversible inhibitor
  • Lung cancer
  • Lung squamous cell carcinoma

ASJC Scopus subject areas

  • Genetics
  • General

Cite this