HER2YVMA drives rapid development of adenosquamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy.
Mutations in the HER2 kinase domain have been identified in human clinical lung cancer specimens. Here we demonstrate that inducible expression of the most common HER2 mutant (HER2(YVMA)) in mouse lung epithelium causes invasive adenosquamous carcinomas restricted to proximal and distal bronchioles. Continuous expression of HER2(YVMA) is essential for tumor maintenance, suggesting a key role for HER2 in lung adenosquamous tumorigenesis. Preclinical studies assessing the in vivo effect of erlotinib, trastuzumab, BIBW2992, and/or rapamycin on HER2(YVMA) transgenic mice or H1781 xenografts with documented tumor burden revealed that the combination of BIBW2992 and rapamycin is the most effective treatment paradigm causing significant tumor shrinkage. Immunohistochemical analysis of lung tumors treated with BIBW2992 and rapamycin combination revealed decreased phosphorylation levels for proteins in both upstream and downstream arms of MAPK and Akt/mTOR signaling axes, indicating inhibition of these pathways. Based on these findings, clinical testing of the BIBW2992/rapamycin combination in non-small cell lung cancer patients with tumors expressing HER2 mutations is warranted.
Perera
Samanthi A
SA
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Li
Danan
D
Shimamura
Takeshi
T
Raso
Maria G
MG
Ji
Hongbin
H
Chen
Liang
L
Borgman
Christa L
CL
Zaghlul
Sara
S
Brandstetter
Kathleyn A
KA
Kubo
Shigeto
S
Takahashi
Masaya
M
Chirieac
Lucian R
LR
Padera
Robert F
RF
Bronson
Roderick T
RT
Shapiro
Geoffrey I
GI
Greulich
Heidi
H
Meyerson
Matthew
M
Guertler
Ulrich
U
Chesa
Pilar Garin
PG
Solca
Flavio
F
Wistuba
Ignacio I
II
Wong
Kwok-Kin
KK
D000077716:Afatinib; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D018196:Carcinoma, Adenosquamous / Q000188:drug therapy*; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use
D000077716:Afatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020123:Sirolimus; C524056:Erbb2 protein, mouse