HER2YVMA drives rapid development of adenosquamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy.

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.

• Authors: 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 Bronson, Geoffrey I Shapiro, Heidi Greulich, Matthew Meyerson, Ulrich Guertler, Pilar Garin Chesa, Flavio Solca, Ignacio I Wistuba, Kwok-Kin Wong
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 106 Issue 2 Pg. 474-9 (Jan 13 2009) ISSN: 1091-6490 [Electronic] United States
• PMID: 19122144 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Quinazolines
• Afatinib
• Erbb2 protein, mouse
• Receptor, ErbB-2
• Sirolimus

Topics

• Afatinib
• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Carcinoma, Adenosquamous (drug therapy)
• Drug Evaluation, Preclinical
• Drug Resistance, Neoplasm
• Lung Neoplasms (drug therapy)
• Mice
• Mutation
• Phosphorylation (drug effects)
• Quinazolines (pharmacology, therapeutic use)
• Receptor, ErbB-2 (genetics, physiology)
• Signal Transduction (drug effects)
• Sirolimus (pharmacology, therapeutic use)