Kinase domain activation of FGFR2 yields high-grade lung adenocarcinoma sensitive to a Pan-FGFR inhibitor in a mouse model of NSCLC.
Kinase domain activation of FGFR2 yields high-grade lung adenocarcinoma sensitive to a Pan-FGFR inhibitor in a mouse model of NSCLC.
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DOI：
10.1158/0008-5472.can-13-3218
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发表时间：
2014-09-01
期刊：
影响因子：
11.2
通讯作者：
Wong KK
中科院分区：
文献类型：
--
作者：
Tchaicha JH;Akbay EA;Altabef A;Mikse OR;Kikuchi E;Rhee K;Liao RG;Bronson RT;Sholl LM;Meyerson M;Hammerman PS;Wong KK
成纤维细胞生长因子受体2(FGFR2)的体细胞突变存在于4%-5%的非小细胞肺癌(NSCLC)患者中。已经在非小细胞肺癌患者中发现了FGFR基因的扩增和突变，临床试验正在测试抗FGFR疗法的疗效。在肺鳞癌和肺腺癌中都发现了FGFR2和其他FGFR激酶家族基因的改变，但FGFR驱动的小鼠肺癌模型尚未见报道。在这里，我们产生了一个非小细胞肺癌的基因工程小鼠模型(GEMM)，该模型是由FGFR2中的激动域突变驱动的。结合P53的消融，在肺上皮室诱导出原发的III/IV级腺癌，表现出以多核细胞为主的局部侵袭性和多向性倾向。肿瘤对PAN-FGFR抑制非常敏感。这是第一个由FGFR2驱动的肺癌GEMM，可以在临床前环境中应用于不同的癌症适应症。
Somatic mutations in Fibroblast Growth Factor Receptor 2 (FGFR2) are present in 4-5% of patients diagnosed with non-small cell lung cancer (NSCLC). Amplification and mutations in FGFR genes have been identified in patients with NSCLC and clinical trials are testing the efficacy of anti-FGFR therapies. FGFR2 and other FGFR kinase family gene alterations have been found in both lung squamous cell carcinoma and lung adenocarcinoma though mouse models of FGFR driven lung cancers have not been reported. Here, we generated a genetically engineered mouse model (GEMM) of NSCLC driven by a kinase domain mutation in FGFR2. Combined with p53 ablation, primary grade III/IV adenocarcinoma was induced in the lung epithelial compartment exhibiting locally invasive and pleiotropic tendencies largely made up of multinucleated cells. Tumors were acutely sensitive to pan-FGFR inhibition. This is the first FGFR2-driven lung cancer GEMM, which can be applied across different cancer indications in a preclinical setting.