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.