The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies.
To understand the role of human epidermal growth factor receptor (hEGFR) kinase domain mutations in lung tumorigenesis and response to EGFR-targeted therapies, we generated bitransgenic mice with inducible expression in type II pneumocytes of two common hEGFR mutants seen in human lung cancer. Both bitransgenic lines developed lung adenocarcinoma after sustained hEGFR mutant expression, confirming their oncogenic potential. Maintenance of these lung tumors was dependent on continued expression of the EGFR mutants. Treatment with small molecule inhibitors (erlotinib or HKI-272) as well as prolonged treatment with a humanized anti-hEGFR antibody (cetuximab) led to dramatic tumor regression. These data suggest that persistent EGFR signaling is required for tumor maintenance in human lung adenocarcinomas expressing EGFR mutants.
Ji
Hongbin
H
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Li
Danan
D
Chen
Liang
L
Shimamura
Takeshi
T
Kobayashi
Susumu
S
McNamara
Kate
K
Mahmood
Umar
U
Mitchell
Albert
A
Sun
Yangping
Y
Al-Hashem
Ruqayyah
R
Chirieac
Lucian R
LR
Padera
Robert
R
Bronson
Roderick T
RT
Kim
William
W
Jänne
Pasi A
PA
Shapiro
Geoffrey I
GI
Tenen
Daniel
D
Johnson
Bruce E
BE
Weissleder
Ralph
R
Sharpless
Norman E
NE
Wong
Kwok-Kin
KK
D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000068818:Cetuximab; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D005091:Exons; D006801:Humans; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D017434:Protein Structure, Tertiary; D011799:Quinazolines / Q000627:therapeutic use; D011804:Quinolines / Q000627:therapeutic use
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D011799:Quinazolines; D011804:Quinolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; C487932:neratinib; D000068818:Cetuximab