HER2YVMA drives rapid development of adenosquamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy.
Document Type
Article
Publication Date
2009
Keywords
Antineoplastic-Combined-Chemotherapy-Protocols, Carcinoma-Adenosquamous, Drug-Evaluation-Preclinical, Drug-Resistance-Neoplasm, Lung-Neoplasms, Mice, Mutation, Phosphorylation, Quinazolines, Receptor-erbB-2, Signal-Transduction, Sirolimus
First Page
474
Last Page
479
JAX Source
Proc Natl Acad Sci U S A 2009 Jan; 106(2):474-9.
Abstract
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.
Recommended Citation
Perera SA,
Li D,
Shimamura T,
Raso MG,
Takahashi M,
Chirieac LR,
Padera RF,
Bronson RT,
et a.
HER2YVMA drives rapid development of adenosquamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy. Proc Natl Acad Sci U S A 2009 Jan; 106(2):474-9.