NSCLC driven by DDR2 mutation is sensitive to dasatinib and JQ1 combination therapy

Chunxiao Xu, Kevin A. Buczkowski, Yanxi Zhang, Hajime Asahina, Ellen M. Beauchamp, Hideki Terai, Yvonne Y. Li, Matthew Meyerson, Kwok Kin Wong, Peter S. Hammerman

研究成果: Article査読

24 被引用数 (Scopus)

抄録

Genetically engineered mouse models of lung cancer have demonstrated an important role in understanding the function of novel lung cancer oncogenes and tumor-suppressor genes identified in genomic studies of human lung cancer. Furthermore, these models are important platforms for preclinical therapeutic studies. Here, we generated a mouse model of lung adenocarcinoma driven by mutation of the discoidin domain receptor 2 (DDR2) gene combined with loss of TP53. DDR2L63V;TP53L/L mice developed poorly differentiated lung adenocarcinomas in all transgenic animals analyzed with a latency of 40 to 50 weeks and a median survival of 67.5 weeks. Mice expressing wild-type DDR2 with combined TP53 loss did not form lung cancers. DDR2L63V; TP53L/L tumors displayed robust expression of DDR2 and immunohistochemical markers of lung adenocarcinoma comparable with previously generated models, though also displayed concomitant expression of the squamous cell markers p63 and SOX2. Tumor-derived cell lines were not solely DDR2 dependent and displayed upregulation of and partial dependence on MYCN. Combined treatment with the multitargeted DDR2 inhibitor dasatinib and BET inhibitor JQ1 inhibited tumor growth in vitro and in vivo. Together, these results suggest that DDR2 mutation can drive lung cancer initiation in vivo and provide a novel mouse model for lung cancer therapeutics studies.

本文言語English
ページ(範囲)2382-2389
ページ数8
ジャーナルMolecular cancer therapeutics
14
10
DOI
出版ステータスPublished - 2015 10 1
外部発表はい

ASJC Scopus subject areas

  • 腫瘍学
  • 癌研究

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