title: The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies.
abstract: 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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Hongbin
authors.initials: H
authors.lastname: Ji
authors.forename: Danan
authors.initials: D
authors.lastname: Li
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimamura
authors.forename: Susumu
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Kate
authors.initials: K
authors.lastname: McNamara
authors.forename: Umar
authors.initials: U
authors.lastname: Mahmood
authors.forename: Albert
authors.initials: A
authors.lastname: Mitchell
authors.forename: Yangping
authors.initials: Y
authors.lastname: Sun
authors.forename: Ruqayyah
authors.initials: R
authors.lastname: Al-Hashem
authors.forename: Lucian R
authors.initials: LR
authors.lastname: Chirieac
authors.forename: Robert
authors.initials: R
authors.lastname: Padera
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.forename: William
authors.initials: W
authors.lastname: Kim
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
authors.forename: Daniel
authors.initials: D
authors.lastname: Tenen
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Johnson
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.forename: Norman E
authors.initials: NE
authors.lastname: Sharpless
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
mesh_terms: 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
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D011799:Quinazolines; D011804:Quinolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; C487932:neratinib; D000068818:Cetuximab