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 Journal Article
| Authors: | Politi, K.; Zakowski, M. F.; Fan, P. D.; Schonfeld, E. A.; Pao, W.; Varmus, H. E. |
| Article 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 (EGFRΔL747-S752) or the L858R mutant (EGFRL858R) 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 EGFRL858R allele show diffuse lung cancer highly reminiscent of human bronchioloalveolar carcinoma and later develop interspersed multifocal adenocarcinomas. In contrast, mice expressing EGFRΔL747-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. © 2006 by Cold Spring Harbor Laboratory Press. |
| Keywords: | histopathology; erlotinib; nonhuman; nuclear magnetic resonance imaging; magnetic resonance imaging; adenocarcinoma; cell proliferation; mouse; animals; mice; animal tissue; apoptosis; gene expression; lung neoplasms; epidermal growth factor receptor; animal experiment; animal model; down-regulation; lung cancer; receptor, epidermal growth factor; tumor regression; drug effect; phosphorylation; carcinogenesis; mus musculus; protein tyrosine kinase inhibitor; lung adenocarcinoma; base sequence; down regulation; protein-tyrosine kinases; dna primers; egfr; tyrosine kinase inhibitor; doxycycline fosfatex |
| Journal Title: | Genes and Development |
| Volume: | 20 |
| Issue: | 11 |
| ISSN: | 0890-9369 |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Date Published: | 2006-06-01 |
| Start Page: | 1496 |
| End Page: | 1510 |
| Language: | English |
| DOI: | 10.1101/gad.1417406 |
| PUBMED: | 16705038 |
| PROVIDER: | scopus |
| PMCID: | PMC1475762 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 155" - "Export Date: 4 June 2012" - "CODEN: GEDEE" - "Source: Scopus" |
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