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

L Regales, MN Balak, Y Gong, K Politi, A Sawai, C Le… - PloS one, 2007 - journals.plos.org
L Regales, MN Balak, Y Gong, K Politi, A Sawai, C Le, JA Koutcher, DB Solit, N Rosen
PloS one, 2007journals.plos.org
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 with a drug-sensitive L858R mutation. Both
transgenic lines develop lung adenocarcinomas that require mutant EGFR for tumor …
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 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. 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/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 EGFRT790M alone or in conjunction with drug-sensitive EGFR kinase domain mutations.
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