NSCLC Driven by DDR2 Mutation is Sensitive to JQ1 and Dasatinib Combination Therapy

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. Further, these models are important platforms for pre-clinical 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 40-50 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 to previously generated models of lung adenocarcinoma though also displayed concomitant expression of the squamous cell markers p63 and SOX2. Tumor-derived cell lines were not solely DDR2 dependent and displayed up-regulation of and partial dependence on MYCN. Combined treatment with the BET inhibitor JQ1 and the mutltitargeted DDR2 inhibitor dasatinib 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. We used microarrays to detail the gene expression profile of mouse primary lung tumor cell lines driven by DDR2L63V;p53L/L and KrasG12D;p53L/L. When DDR2L63V; p53 and KrasG12D;p53L/L mice developed lung tumors confirmed by MRI, the mice were sacrificed and lung tumor nodules were harvested, finely minced, and cultured in 100 mm dishes with RPMI 1640/10% FBS/1% pen-strep/2mM L-Glutamine. After 3 passages, frozen stocks of these short-term cultures were prepared, and further characterized by genotyping. DDR2 expression was induced by treating cells with 2 ug/ml DOX every 2 to 3 days and confirmed by western blot analysis. The cells were cultured in RPMI 1640/10% FBS/1% pen-strep/2mM L-Glutamine. All cells were cultured at 37oC in a humidified incubator with 5% CO2.