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.


RESULTS
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
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.
Regales
Lucia
L
Pao Lab, Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
Balak
Marissa N
MN
Gong
Yixuan
Y
Politi
Katerina
K
Sawai
Ayana
A
Le
Carl
C
Koutcher
Jason A
JA
Solit
David B
DB
Rosen
Neal
N
Zakowski
Maureen F
MF
Pao
William
W
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016227:Benzoquinones / Q000494:pharmacology; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D047428:Protein Kinase Inhibitors; C112765:tanespimycin; C541485:EGFR protein, mouse; D066246:ErbB Receptors