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. 2015 Oct;14(10):2382-2389.
doi: 10.1158/1535-7163.MCT-15-0077. Epub 2015 Jul 23.

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

Chunxiao Xu #  1   2 , Kevin A Buczkowski #  1 , Yanxi Zhang  1   2 , Hajime Asahina  1   2 , Ellen M Beauchamp  1 , Hideki Terai  1 , Yvonne Y Li  1   3 , Matthew Meyerson  1   4   3   5 , Kwok-Kin Wong  1   2 , Peter S Hammerman  1   3
Affiliations

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

Chunxiao Xu et al. Mol Cancer Ther. 2015 Oct.

Abstract

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. DDR2(L63V);TP53(L/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. DDR2(L63V);TP53(L/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.

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Figures

Figure 1
Figure 1. Generation and characterization of the genetically engineered mice with inducible expression of DDR2L63V and TP53 deletion in the lung
A. Schema of the DDR2 construct, cross strategy and induction for the conditional transgenic mice. B. Kaplan-Meyer survival analysis of DDR2;p53 mice following intra-nasal Ad-Cre instillation and DOX administration. All death was caused by tumor burden. Median survival of DDR2L63V;p53= 67.5 weeks. C. Representative H&E-stained sections derived from tumors arising in the DDR2L63V;p53 mouse model at different time points after DOX and Ad-Cre administration. D. Immunohistochemical staining of DDR2 on tumor nodules driven by DDR2L63V;p53 and EGFRT 790M-L858R. Scale bars represent 100 mm for all panels.
Figure 2
Figure 2. NSCLC driven by DDR2L63V displays a mixed phenotype
Immunohistochemical staining of tumor nodules of DDR2L63V;p53 mice, the SCC canonical markers p63 and SOX2, and the ADC canonical marker TTF1 were used to distinguish the tumor types. Scale bars represent 100 mm for all panels.
Figure 3
Figure 3. MYCN is elevated in DDR2L63V tumors
A. Immunoblot analysis of DDR2 levels in uninduced and DOX induced cell lines (3941 and 3942) from DDR2 transgenic tumors. The 855 line was previously derived from a murine lung adenocarcinoma from a Kras;p53 mouse. B. Microarray expression profiling of mouse DDR2L63V;p53 (3941 and 3942) and Kras;p53 cell lines (634, 855 and 858); Heatmap depicts elevated expression of selected genes in DDR2L63V;p53 lines. C. Immunoblot analysis of NMYC in DDR2L63V;p53 cell lines vs Kras;p53 cell lines. D. Immunoblot analysis of NMYC knockdown (“+” indicates siRNA knockdown and “−” a non-targeting siRNA). E. Proliferation assay of a Kras;p53 cell line (858) compared to the DDR2L63V;p53 cell line (3941) 24 and 48 hours after siRNA mediated NMYC knockdown. Control indicates a non-targeting siRNA control.
Figure 4
Figure 4. NSCLC driven by DDR2L63V is sensitive to dasatinib and JQ1 combination therapy
A. Proliferation of Kras;p53 cell lines 858, and DDR2L63V;p53 cell line 3941 grown for 5 days in the presence of varying concentrations of dasatinib, JQ1 and a combination of 1μM JQ1 and varying dasatinib concentrations. B, C. Tumor volume measurement in a xenograft study of the DDR2L63V;p53 (3941) lung cancer cell line. Nu/Nu mice were treated with dasatinib, JQ1, and dasatinib plus JQ1 combination for 3 weeks following tumor formation. B. Average tumor volumes; C. Harvested tumor nodules sizes;
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