Development of new mouse lung tumor models expressing EGFR T790M mutants associated with clinical resistance to kinase inhibitors

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 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. 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/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 EGFR^T790M alone or in conjunctio with drug-sensitive EGFR kinase domain mutations.