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

被引：139

作者：

Perera, Samanthi A.

Li, Danan

Shimamura, Takeshi

Raso, Maria G. ^{[2
]}

Ji, Hongbin ^{[4
]}

Chen, Liang

Borgman, Christa L.

Zaghlul, Sara

Brandstetter, Kathleyn A.

Kubo, Shigeto ^{[5
]}

Takahashi, Masaya

Chirieac, Lucian R. ^{[6
]}

Padera, Robert F. ^{[6
]}

Bronson, Roderick T. ^{[7
]}

Shapiro, Geoffrey I.

Greulich, Heidi ^{[8
]}

Meyerson, Matthew ^{[8
]}

Guertler, Ulrich ^{[9
]}

Chesa, Pilar Garin ^{[9
]}

Solca, Flavio ^{[9
]}

Wistuba, Ignacio I. ^{[2
,3
]}

Wong, Kwok-Kin ^{[1
]}

机构：

[1] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol,Lowe Ctr Thorac Oncol, Boston, MA 02115 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Houston, TX 77030 USA

[4] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Mol Cell Biol Lab, Shanghai 200031, Peoples R China

[5] Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA 02115 USA

[6] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[7] Harvard Univ, Dept Pathol, Boston, MA 02115 USA

[8] Broad Inst MIT & Harvard, Boston, MA 02115 USA

[9] Boehringer Ingelheim GmbH & Co KG, Dept Pharmacol, A-1120 Vienna, Austria

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2009年 / 106卷 / 02期

基金：

美国国家卫生研究院;

关键词：

lung cancer; murine model; HER2 KINASE DOMAIN; EGFR; MUTATIONS; TRASTUZUMAB; ERBB2; ACTIVATION; CARCINOMA;

D O I：

10.1073/pnas.0808930106

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 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 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.

引用

页码：474 / 479

页数：6

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