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HER2YVMA Drives Rapid Development of Adenosquamous Lung Tumors in Mice That Are Sensitive to BIBW2992 and Rapamycin Combination Therapy
Samanthi A. Perera, Danan Li, Takeshi Shimamura, Maria G. Raso, Hongbin Ji, Liang Chen, Christa L. Borgman, Sara Zaghlul, Kathleyn A. Brandstetter, Shigeto Kubo, Masaya Takahashi, Lucian R. Chirieac, Robert F. Padera, Roderick T. Branson, Geoffrey I. Shapiro, Heidi Greulich, Matthew Meyerson, Ulrich Guertler, Pilar Garin Chesa, Flavio Solca, Ignacio I. Wistuba, Kwok-Kin Wong and Webster K. Cavenee
Proceedings of the National Academy of Sciences of the United States of America
Vol. 106, No. 2 (Jan. 13, 2009), pp. 474-479
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/40254804
Page Count: 6
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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 HER2YVMA in mouse lung epithelium causes invasive adenosquamous carcinomas restricted to proximal and distal bronchioles. Continuous expression of HER2YVMA 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 HER2YVMA 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.
Proceedings of the National Academy of Sciences of the United States of America © 2009 National Academy of Sciences