Cholangiocarcinoma, originating from the biliary duct, represents a subset of liver cancer. With about 8000 new cases of cholangiocarcinoma diagnosed annually in the U.S., these fall into three categories: intrahepatic, peri-hilar, and extrahepatic cholangiocarcinoma. Arising from the epithelium of the bile duct, intrahepatic cholangiocarcinoma (ICC) is a universally fatal malignancy with very few treatment options. The poor prognosis and lack of molecular targeted therapies highlights ICC as a critical unmet medical need. With advances in sequencing technology, numerous chromosomal translocations have been discovered as drivers in cancer initiation and progression. Particularly in ICC, chromosomal translocations involving Fibroblast Growth Factor Receptor 2 (FGFR2) have been frequently identified, resulting in the creation of oncogenic fusion proteins. At the N-terminus, these fusion proteins share a nearly-identical FGFR2 moiety retaining an intact kinase domain and, at the C-terminus, a dimerization/oligomerization domain provided by different partner genes, including: Periphilin 1 (PPHLN1), Bicaudal family RNA binding protein 1 (BICC1), Adenosylhomocysteinase Like 1 (AHCYL1), and Transforming Acidic Coiled-Coil Containing Protein 3 (TACC3). A number of pre-clinical and clinical trials have shown the effectiveness of FGFR inhibitors in treating FGFR2 fusion-positive ICC patients. However, the efficacy of these inhibitors may be short-lived due to acquired resistance. In this review, we provide an overview of FGFR2 fusions, comparing their structures and mechanism of dimerization, examining the importance of FGFR2 as a partner gene, as well as highlighting the significance of alternative splicing of FGFR2 in these fusion proteins. In addition, we discuss various therapeutic options and their associated potencies in targeting these translocation-induced ICCs.

中文翻译：

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在肝内胆管癌中，FGFR2的功能因易位而受损。

胆管癌起源于胆管，代表肝癌的一个子集。在美国，每年约有8000例新诊断的胆管癌病例，分为三类：肝内，肝门周围和肝外胆管癌。肝内胆管癌（ICC）由胆管上皮引起，是一种普遍致命的恶性肿瘤，几乎没有治疗选择。预后差和缺乏分子靶向疗法突出了ICC是一项关键的未满足的医疗需求。随着测序技术的进步，已发现许多染色体易位是癌症发生和发展的驱动力。特别是在ICC中，涉及成纤维细胞生长因子受体2（FGFR2）的染色体易位已被频繁鉴定，导致产生致癌融合蛋白。在N端，这些融合蛋白共享几乎相同的FGFR2部分，保留完整的激酶结构域；在C端，由不同伴侣基因提供的二聚化/低聚结构域，包括：亲缘素1（PPHLN1），比卡多家族RNA结合蛋白1（BICC1），腺苷同型半胱氨酸酶类似物1（AHCYL1）和转化酸性含线圈蛋白3（TACC3）。许多临床前和临床试验表明FGFR抑制剂可有效治疗FGFR2融合阳性ICC患者。然而，由于获得性抗性，这些抑制剂的功效可能是短暂的。在这篇综述中，我们提供了FGFR2融合的概述，比较了它们的结构和二聚化机制，研究了FGFR2作为伴侣基因的重要性，并强调了在这些融合蛋白中FGFR2选择性剪接的重要性。此外，我们讨论了针对这些易位诱导的ICC的各种治疗选择及其相关功效。