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. Bronson, Geoffrey I. Shapiro, Heidi Greulich, Matthew Meyerson, Ulrich Guertler, Pilar Garin Chesa, Flavio SolcaIgnacio I. Wistuba, Kwok Kin Wong

Research output: Contribution to journalArticle

119 Citations (Scopus)

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 (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.

Original languageEnglish (US)
Pages (from-to)474-479
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number2
DOIs
StatePublished - Jan 13 2009

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Sirolimus
Lung
Neoplasms
Adenosquamous Carcinoma
Bronchioles
Mutation
Therapeutics
Tumor Burden
Heterografts
Non-Small Cell Lung Carcinoma
Transgenic Mice
Lung Neoplasms
Carcinogenesis
Arm
Phosphotransferases
Epithelium
Maintenance
Phosphorylation
BIBW 2992
Proteins

Keywords

  • Lung cancer
  • Murine model

ASJC Scopus subject areas

  • General

Cite this

HER2YVMA drives rapid development of adenosquamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy. / Perera, Samanthi A.; Li, Danan; Shimamura, Takeshi; Raso, Maria G.; Ji, Hongbin; Chen, Liang; Borgman, Christa L.; Zaghlul, Sara; Brandstetter, Kathleyn A.; Kubo, Shigeto; Takahashi, Masaya; Chirieac, Lucian R.; Padera, Robert F.; Bronson, Roderick T.; Shapiro, Geoffrey I.; Greulich, Heidi; Meyerson, Matthew; Guertler, Ulrich; Chesa, Pilar Garin; Solca, Flavio; Wistuba, Ignacio I.; Wong, Kwok Kin.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 2, 13.01.2009, p. 474-479.

Research output: Contribution to journalArticle

Perera, SA, Li, D, Shimamura, T, Raso, MG, Ji, H, Chen, L, Borgman, CL, Zaghlul, S, Brandstetter, KA, Kubo, S, Takahashi, M, Chirieac, LR, Padera, RF, Bronson, RT, Shapiro, GI, Greulich, H, Meyerson, M, Guertler, U, Chesa, PG, Solca, F, Wistuba, II & Wong, KK 2009, 'HER2YVMA drives rapid development of adenosquamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy', Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 2, pp. 474-479. https://doi.org/10.1073/pnas.0808930106
Perera, Samanthi A. ; Li, Danan ; Shimamura, Takeshi ; Raso, Maria G. ; Ji, Hongbin ; Chen, Liang ; Borgman, Christa L. ; Zaghlul, Sara ; Brandstetter, Kathleyn A. ; Kubo, Shigeto ; Takahashi, Masaya ; Chirieac, Lucian R. ; Padera, Robert F. ; Bronson, Roderick T. ; Shapiro, Geoffrey I. ; Greulich, Heidi ; Meyerson, Matthew ; Guertler, Ulrich ; Chesa, Pilar Garin ; Solca, Flavio ; Wistuba, Ignacio I. ; Wong, Kwok Kin. / HER2YVMA drives rapid development of adenosquamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 2. pp. 474-479.
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AU - Shimamura, Takeshi

AU - Raso, Maria G.

AU - Ji, Hongbin

AU - Chen, Liang

AU - Borgman, Christa L.

AU - Zaghlul, Sara

AU - Brandstetter, Kathleyn A.

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AU - Takahashi, Masaya

AU - Chirieac, Lucian R.

AU - Padera, Robert F.

AU - Bronson, Roderick T.

AU - Shapiro, Geoffrey I.

AU - Greulich, Heidi

AU - Meyerson, Matthew

AU - Guertler, Ulrich

AU - Chesa, Pilar Garin

AU - Solca, Flavio

AU - Wistuba, Ignacio I.

AU - Wong, Kwok Kin

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N2 - 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.

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