Authors: | Regales, L.; Balak, M. N.; Gong, Y.; Politi, K.; Sawai, A.; Le, C.; Koutcher, J. A.; Solit, D. B.; Rosen, N.; Zakowski, M. F.; Pao, W. |
Article Title: | Development of new mouse lung tumor models expressing EGFR T790M mutants associated with clinical resistance to kinase inhibitors |
Abstract: | Background: The EGFR T790M mutation confers acquired resistance to kinase inhibitors in human EGFR mutant lung adenocarcinoma, is occasionally detected before treatment, and may confer genetic susceptibility to lung cancer. Methodology/Principal Findings: To study further its role in lung tumorigenesis, we developed mice with inducible expression in type II pneumocytes of EGFRT790M alone or together witb a drug-sensitive L858R mutation. Both transgenic lines develop lung adenocarcinomas that require mutarst EGFR for turmor maintenance but are resistant to an EGFR kinase inhibitor. EGFRL858R-T790M-driven tumors are transiently targeted by hsp90 inhibition. Notably, EGFRT790M-expressing animals develop tumors with longer latency than EGFRL858R-T790M-bearing mice and in the absence of additional kinase domain mutations. Conclusions/Signifance: These new mouse models of mutant EGFR-dependent lung adenocarcinomas provide insight into clinical observations. The models should also be useful for developing improved therapies for patients with lung cancers harboring EGFRT790M alone or in conjunctio with drug-sensitive EGFR kinase domain mutations. © 2007 Regales et al. |
Keywords: | immunohistochemistry; controlled study; protein expression; gene mutation; genetics; mutation; erlotinib; placebo; dose response; drug efficacy; nonhuman; antineoplastic agents; nuclear magnetic resonance imaging; antineoplastic agent; protein domain; mouse; animal; metabolism; animals; mice; animal tissue; mus; amino acid substitution; protein kinase inhibitor; lung neoplasms; epidermal growth factor receptor; animal experiment; animal model; genotype; receptor, epidermal growth factor; antineoplastic activity; drug resistance; drug resistance, neoplasm; transgenic mouse; animalia; mice, transgenic; cancer resistance; protein kinase inhibitors; disease model; lung tumor; drug antagonism; lung adenocarcinoma; transgene; immunoblotting; tanespimycin; heat shock protein 90; hsp90 heat-shock proteins; lung carcinogenesis; disease models, animal; doxycycline; benzoquinones; lactams, macrocyclic; epidermal growth factor receptor kinase inhibitor; 17-(allylamino)-17-demethoxygeldanamycin; benzoquinone derivative; macrocyclic lactam; protein c; lung alveolus cell type 2; egfr protein, mouse; lung structure |
Journal Title: | PLoS ONE |
Volume: | 2 |
Issue: | 8 |
ISSN: | 1932-6203 |
Publisher: | Public Library of Science |
Date Published: | 2007-08-29 |
Start Page: | e810 |
Language: | English |
DOI: | 10.1371/journal.pone.0000810 |
PUBMED: | 17726540 |
PROVIDER: | scopus |
PMCID: | PMC1950079 |
DOI/URL: | |
Notes: | Erratum published at DOI: 10.1371/journal.pone.0323763 - "Cited By (since 1996): 28" - "Export Date: 17 November 2011" - "Source: Scopus" |