Data from NSCLC Driven by <i>DDR2</i> Mutation Is Sensitive to Dasatinib and JQ1 Combination Therapy

Abstract

<div>Abstract<p>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 (<i>DDR2</i>) gene combined with loss of <i>TP53. DDR2<sup>L63V</sup></i>;<i>TP5</i>3<sup>L/L</sup> 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 <i>DDR2</i> with combined <i>TP53</i> loss did not form lung cancers. <i>DDR2<sup>L63V</sup></i>;<i>TP5</i>3<sup>L/L</sup> 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 <i>DDR2</i> dependent and displayed upregulation of and partial dependence on <i>MYCN</i>. Combined treatment with the multitargeted DDR2 inhibitor dasatinib and BET inhibitor JQ1 inhibited tumor growth <i>in vitro</i> and <i>in vivo</i>. Together, these results suggest that <i>DDR2</i> mutation can drive lung cancer initiation <i>in vivo</i> and provide a novel mouse model for lung cancer therapeutics studies. <i>Mol Cancer Ther; 14(10); 2382–9. ©2015 AACR</i>.</p></div>