Transgenic mice with mouse EGFR mutation developed lung adenocarcinoma

LB-106 Human epidermal growth factor receptor (EGFR) mutations are reported to trigger adenocarcinoma of the lung in transgenic mice, but further details regarding the carcinogenic process are needed. To investigate the role of EGFR and signal pathway in the lungs, we tried to generate transgenic mice with mouse EGFR mutation (L860R and delE748-A752) which corresponded to human EGFR mutation (L858R and delE746-A750), respectively. To express mouse EGFR mutation continuously only on the type II pneumocyte, we employed SPC promoter. Our transgenic line with EGFR mutation (delE748-A752) overexpressed EGFR mRNA and protein when compared to the control mice. Additionally, they produced multifocal adenocarcinoma of the lung at around 6 weeks of age and, without treatment, died of adenocarcinoma of the lung at around 16 weeks of age. Treatment with the EGFR tyrosine kinase inhibitor (TKI), gefitinib (5 mg/kg/day), or the EGFR and vascular endothelial growth factor receptor (VEGFR) TKI, vandetanib (5 mg/kg/day), markedly reduced phosphorylated EGFR to almost the same level as that of lung tissue in the control mice. The tumors disappeared within a week. The mice treated with gefitinib had a prolonged survival time of 30 weeks or more. The control mice have survived over one year without lung cancer. This model may be useful for developing improved therapies for lung cancer and investigating mechanisms of resistance to EGFR TKIs. This work is a collaborative effort with Dr. Jeffrey Whitsett, Cincinnati Children9s Hospital Medical Center.