Induction of lung adenocarcinoma in transgenic mice expressing activated EGFR driven by the SP-C promoter.
To investigate the role of an activating epidermal growth factor receptor (EGFR) mutation in lung cancer, we generated transgenic mice expressing the delE748-A752 mutant version of mouse EGFR driven by the SP-C promoter, which is equivalent to the delE746-A750 mutation found in lung cancer patients. Strikingly, the mice invariably developed multifocal lung adenocarcinomas of varying sizes at between 5 and 6 weeks of age, and they died from tumor progression approximately 2 months later if left untreated. Daily oral administration of the EGFR tyrosine kinase inhibitor (TKI) gefitinib (5 mg/kg/day) reduced the total and phosphorylation levels of EGFR to those in wild-type mouse lung tissue; in addition, it abrogated tumor growth within 1 week and prolonged survival to >30 weeks. Interestingly, phosphorylated ErbB2, ErbB3, and thyroid transcriptional factor-1 increased in the transgenic mice compared with those in wild-type mice. They might play some roles in tumors progression in the transgenic mice. This model will be useful for studying the mechanisms of carcinogenesis, chemoprevention, and acquired resistance to EGFR TKIs in lung cancer patients carrying activating EGFR mutations.
Ohashi
Kadoaki
K
Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
Rai
Kammei
K
Fujiwara
Yoshiro
Y
Osawa
Masahiro
M
Hirano
Seiki
S
Takata
Katsuyoshi
K
Kondo
Eisaku
E
Yoshino
Tadashi
T
Takata
Minoru
M
Tanimoto
Mitsune
M
Kiura
Katsuyuki
K
D000230:Adenocarcinoma / Q000235:genetics*; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics; D005260:Female; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D018773:Genes, erbB-1 / Q000235:genetics*; D036341:Intercellular Signaling Peptides and Proteins; D008175:Lung Neoplasms / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D010455:Peptides / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D037721:Pulmonary Surfactant-Associated Protein C; D011799:Quinazolines / Q000494:pharmacology
D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D047428:Protein Kinase Inhibitors; D037721:Pulmonary Surfactant-Associated Protein C; D011799:Quinazolines; C489680:Sftpc protein, mouse; D000077156:Gefitinib