title: Lung adenocarcinomas induced in mice by mutant EGF receptors found in human lung cancers respond to a tyrosine kinase inhibitor or to down-regulation of the receptors.
abstract: 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.
authors.affiliation: Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. politik@mskcc.org
authors.forename: Katerina
authors.initials: K
authors.lastname: Politi
authors.forename: Maureen F
authors.initials: MF
authors.lastname: Zakowski
authors.forename: Pang-Dian
authors.initials: PD
authors.lastname: Fan
authors.forename: Emily A
authors.initials: EA
authors.lastname: Schonfeld
authors.forename: William
authors.initials: W
authors.lastname: Pao
authors.forename: Harold E
authors.initials: HE
authors.lastname: Varmus
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D015536:Down-Regulation; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008279:Magnetic Resonance Imaging; D051379:Mice; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D017931:DNA Primers; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases