NSCLC Driven by DDR2 Mutation Is Sensitive to Dasatinib and JQ1 Combination Therapy.
NSCLC Driven by DDR2 Mutation Is Sensitive to Dasatinib and JQ1 Combination Therapy.
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DOI：
10.1158/1535-7163.mct-15-0077
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发表时间：
2015-10
影响因子：
5.7
通讯作者：
Hammerman PS
中科院分区：
文献类型：
--
作者：
Xu C;Buczkowski KA;Zhang Y;Asahina H;Beauchamp EM;Terai H;Li YY;Meyerson M;Wong KK;Hammerman PS
基因工程小鼠肺癌模型在了解人类肺癌基因组研究中发现的新的肺癌癌基因和肿瘤抑制基因的功能方面发挥了重要作用。此外，这些模型是临床前治疗研究的重要平台。在这里，我们建立了一种由盘状结构域受体2(DDR2)基因突变和TP53缺失共同驱动的小鼠肺腺癌模型。在所有转基因动物中，DDR2L63V；TP53L/L小鼠均发生低分化肺腺癌，分析其潜伏期为40-50周，中位生存期为67.5周。表达野生型DDR2并伴有TP53缺失的小鼠没有形成肺癌。与先前建立的模型相比，DDR2L63V；TP53L/L肿瘤模型显示出与肺腺癌相似的DDR2和免疫组织化学标志物的强阳性表达，但同时也显示出鳞状细胞标志物P63和SOX2的表达。肿瘤来源的细胞系并不完全依赖于DDR2，并且对MYCN表现出上调和部分依赖。多靶点DDR2抑制剂达沙替尼和BET抑制剂JQ1联合治疗在体外和体内均可抑制肿瘤生长。综上所述，这些结果表明，DDR2突变可以在体内驱动肺癌的发生，为肺癌治疗研究提供了一种新的小鼠模型。
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 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 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.