Bronchial and peripheral murine lung carcinomas induced by T790M-L858R mutant EGFR respond to HKI-272 and rapamycin combination therapy.
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.
Li
Danan
D
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Shimamura
Takeshi
T
Ji
Hongbin
H
Chen
Liang
L
Haringsma
Henry J
HJ
McNamara
Kate
K
Liang
Mei-Chih
MC
Perera
Samanthi A
SA
Zaghlul
Sara
S
Borgman
Christa L
CL
Kubo
Shigeto
S
Takahashi
Masaya
M
Sun
Yanping
Y
Chirieac
Lucian R
LR
Padera
Robert F
RF
Lindeman
Neal I
NI
Jänne
Pasi A
PA
Thomas
Roman K
RK
Meyerson
Matthew L
ML
Eck
Michael J
MJ
Engelman
Jeffrey A
JA
Shapiro
Geoffrey I
GI
Wong
Kwok-Kin
KK
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
D011804:Quinolines; D066246:ErbB Receptors; C487932:neratinib; D020123:Sirolimus