Somatic mutations in exons encoding the tyrosine kinase domain of the epidermal 
growth factor receptor (EGFR) gene are found in human lung adenocarcinomas and 
are associated with sensitivity to the tyrosine kinase inhibitors gefitinib and 
erlotinib. Nearly 90% of the EGFR mutations are either short, in-frame deletions 
in exon 19 or point mutations that result in substitution of arginine for 
leucine at amino acid 858 (L858R). To study further the role of these mutations 
in the initiation and maintenance of lung cancer, we have developed transgenic 
mice that express an exon 19 deletion mutant (EGFR(DeltaL747-S752)) or the L858R 
mutant (EGFR(L858R)) in type II pneumocytes under the control of doxycycline. 
Expression of either EGFR mutant leads to the development of lung 
adenocarcinomas. Two weeks after induction with doxycycline, mice that express 
the EGFR(L858R) allele show diffuse lung cancer highly reminiscent of human 
bronchioloalveolar carcinoma and later develop interspersed multifocal 
adenocarcinomas. In contrast, mice expressing EGFR(DeltaL747-S752) develop 
multifocal tumors embedded in normal lung parenchyma with a longer latency. With 
mice carrying either EGFR allele, withdrawal of doxycycline (to reduce 
expression of the transgene) or treatment with erlotinib (to inhibit kinase 
activity) causes rapid tumor regression, as assessed by magnetic resonance 
imaging and histopathology, demonstrating that mutant EGFR is required for tumor 
maintenance. These models may be useful for developing improved therapies for 
patients with lung cancers bearing EGFR mutations.