The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies

Hongbin Ji, Danan Li, Liang Chen, Takeshi Shimamura, Susumu Kobayashi, Kate McNamara, Umar Mahmood, Albert Mitchell, Yangping Sun, Ruqayyah Al-Hashem, Lucian R. Chirieac, Robert Padera, Roderick T. Bronson, William Kim, Pasi A. Jänne, Geoffrey I. Shapiro, Daniel Tenen, Bruce E. Johnson, Ralph Weissleder, Norman E. SharplessKwok Kin Wong

Research output: Contribution to journalArticlepeer-review

387 Scopus citations

Abstract

To understand the role of human epidermal growth factor receptor (hEGFR) kinase domain mutations in lung tumorigenesis and response to EGFR-targeted therapies, we generated bitransgenic mice with inducible expression in type II pneumocytes of two common hEGFR mutants seen in human lung cancer. Both bitransgenic lines developed lung adenocarcinoma after sustained hEGFR mutant expression, confirming their oncogenic potential. Maintenance of these lung tumors was dependent on continued expression of the EGFR mutants. Treatment with small molecule inhibitors (erlotinib or HKI-272) as well as prolonged treatment with a humanized anti-hEGFR antibody (cetuximab) led to dramatic tumor regression. These data suggest that persistent EGFR signaling is required for tumor maintenance in human lung adenocarcinomas expressing EGFR mutants.

Original languageEnglish
Pages (from-to)485-495
Number of pages11
JournalCancer Cell
Volume9
Issue number6
DOIs
StatePublished - 13 Jun 2006
Externally publishedYes

Keywords

  • CELLCYCLE
  • PROTEINS
  • SIGNALING

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