Antitumor effect of FGFR inhibitors on a novel cholangiocarcinoma patient derived xenograft mouse model endogenously expressing an FGFR2-CCDC6 fusion protein.
Antitumor effect of FGFR inhibitors on a novel cholangiocarcinoma patient derived xenograft mouse model endogenously expressing an FGFR2-CCDC6 fusion protein.
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DOI：
10.1016/j.canlet.2016.05.017
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发表时间：
2016-09-28
期刊：
影响因子：
9.7
通讯作者：
Roberts, Lewis R.
中科院分区：
文献类型：
--
作者：
Wang, Yu;Ding, Xiwei;Wang, Shaoqing;Moser, Catherine D.;Shaleh, Hassan M.;Mohamed, Essa A.;Chaiteerakij, Roongruedee;Allotey, Loretta K.;Chen, Gang;Miyabe, Katsuyuki;McNulty, Melissa S.;Ndzengue, Albert;Fritcher, Emily G. Barr;Knudson, Ryan A.;Greipp, Patricia T.;Clark, Karl J.;Torbenson, Michael S.;Kipp, Benjamin R.;Zhou, Jie;Barrett, Michael T.;Gustafson, Michael P.;Alberts, Steven R.;Borad, Mitesh J.;Roberts, Lewis R.
胆管癌是一种高度致命的癌症，治疗选择有限。最近的胆管癌基因组分析显示，在高达13%的肝内胆管癌（iCCA）中存在成纤维细胞生长因子受体2（FGFR 2）融合蛋白。FGFR融合体已被鉴定为许多癌症中的新型致癌和可药物化靶标。在这项研究中，我们建立了一种新的胆管癌患者来源的异种移植物（PDX）小鼠模型，该模型携带来自iCCA患者转移性肺结节的FGFR 2-CCDC 6融合蛋白。使用该PDX模型，我们证实了FGFR抑制剂泊那替尼、dovitinib和BGJ 398在携带FGFR 2融合的胆管癌肿瘤中调节FGFR信号传导、抑制细胞增殖和诱导细胞凋亡的能力。此外，在该模型中，BGJ 398的效力似乎上级泊那替尼和多韦替尼。我们的研究结果为研究FGFR抑制剂，特别是BGJ 398，作为携带FGFR 2融合的胆管癌患者的治疗选择提供了强有力的理论基础。
Cholangiocarcinoma is a highly lethal cancer with limited therapeutic options. Recent genomic analysis of cholangiocarcinoma has revealed the presence of fibroblast growth factor receptor 2 (FGFR2) fusion proteins in up to 13% of intrahepatic cholangiocarcinoma (iCCA). FGFR fusions have been identified as a novel oncogenic and druggable target in a number of cancers. In this study, we established a novel cholangiocarcinoma patient derived xenograft (PDX) mouse model bearing an FGFR2-CCDC6 fusion protein from a metastatic lung nodule of an iCCA patient. Using this PDX model, we confirmed the ability of the FGFR inhibitors, ponatinib, dovitinib and BGJ398, to modulate FGFR signaling, inhibit cell proliferation and induce cell apoptosis in cholangiocarcinoma tumors harboring FGFR2 fusions. In addition, BGJ398 appeared to be superior in potency to ponatinib and dovitinib in this model. Our findings provide a strong rationale for the investigation of FGFR inhibitors, particularly BGJ398, as a therapeutic option for cholangiocarcinoma patients harboring FGFR2 fusions.
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