Open AccessDevelopment of New Mouse Lung Tumor Models Expressing EGFR T790M Mutants Associated with Clinical Resistance to Kinase Inhibitors
Author(s) -
Lucía Regales,
Marissa N. Balak,
Yixuan Gong,
Katerina Politi,
Ayana Sawai,
Carl Le,
Jason A. Koutcher,
David B. Solit,
Neal Rosen,
Maureen F. Zakowski,
William Pao
Publication year - 2007
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0000810
Subject(s) - t790m , cancer research , protein kinase domain , lung cancer , adenocarcinoma , mutant , epidermal growth factor receptor , egfr inhibitors , biology , mutation , kinase , medicine , cancer , pathology , gefitinib , gene , genetics
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 EGFR T790M alone or together with a drug-sensitive L858R mutation. Both transgenic lines develop lung adenocarcinomas that require mutant EGFR for tumor maintenance but are resistant to an EGFR kinase inhibitor. EGFR L858R+T790M -driven tumors are transiently targeted by hsp90 inhibition. Notably, EGFR T790M -expressing animals develop tumors with longer latency than EGFR L858R+T790M -bearing mice and in the absence of additional kinase domain mutations. Conclusions/Significance 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 EGFR T790M alone or in conjunction with drug-sensitive EGFR kinase domain mutations.