title: Bronchial and peripheral murine lung carcinomas induced by T790M-L858R mutant EGFR respond to HKI-272 and rapamycin combination therapy.
abstract: The EGFR T790M mutation has been identified in tumors from lung cancer patients that eventually develop resistance to erlotinib. In this study, we generated a mouse model with doxycycline-inducible expression of a mutant EGFR containing both L858R, an erlotinib-sensitizing mutation, and the T790M resistance mutation (EGFR TL). Expression of EGFR TL led to development of peripheral adenocarcinomas with bronchioloalveolar features in alveoli as well as papillary adenocarcinomas in bronchioles. Treatment with an irreversible EGFR tyrosine kinase inhibitor (TKI), HKI-272, shrunk only peripheral tumors but not bronchial tumors. However, the combination of HKI-272 and rapamycin resulted in significant regression of both types of lung tumors. This combination therapy may potentially benefit lung cancer patients with the EGFR T790M mutation.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Danan
authors.initials: D
authors.lastname: Li
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimamura
authors.forename: Hongbin
authors.initials: H
authors.lastname: Ji
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Haringsma
authors.forename: Kate
authors.initials: K
authors.lastname: McNamara
authors.forename: Mei-Chih
authors.initials: MC
authors.lastname: Liang
authors.forename: Samanthi A
authors.initials: SA
authors.lastname: Perera
authors.forename: Sara
authors.initials: S
authors.lastname: Zaghlul
authors.forename: Christa L
authors.initials: CL
authors.lastname: Borgman
authors.forename: Shigeto
authors.initials: S
authors.lastname: Kubo
authors.forename: Masaya
authors.initials: M
authors.lastname: Takahashi
authors.forename: Yanping
authors.initials: Y
authors.lastname: Sun
authors.forename: Lucian R
authors.initials: LR
authors.lastname: Chirieac
authors.forename: Robert F
authors.initials: RF
authors.lastname: Padera
authors.forename: Neal I
authors.initials: NI
authors.lastname: Lindeman
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.forename: Roman K
authors.initials: RK
authors.lastname: Thomas
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Meyerson
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Eck
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001984:Bronchial Neoplasms / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D051379:Mice; D009154:Mutation; D011804:Quinolines / Q000008:administration & dosage; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020123:Sirolimus / Q000008:administration & dosage
chemical_list: D011804:Quinolines; D066246:ErbB Receptors; C487932:neratinib; D020123:Sirolimus