王敏, 张谨阳, 王雨薇, 李雯, 孙丽萍*. FGFR4:一种有望治疗肝癌的靶点J. 药学学报, 2021,56(7): 1832-1844. doi: 10.16438/j.0513-4870.2020-1944
引用本文: 王敏, 张谨阳, 王雨薇, 李雯, 孙丽萍*. FGFR4:一种有望治疗肝癌的靶点J. 药学学报, 2021,56(7): 1832-1844. doi: 10.16438/j.0513-4870.2020-1944
WANG Min, ZHANG Jin-yang, WANG Yu-wei, LI Wen, SUN Li-ping*. FGFR4: a promising therapeutic target for liver cancerJ. Acta Pharmaceutica Sinica, 2021,56(7): 1832-1844. doi: 10.16438/j.0513-4870.2020-1944
Citation: WANG Min, ZHANG Jin-yang, WANG Yu-wei, LI Wen, SUN Li-ping*. FGFR4: a promising therapeutic target for liver cancerJ. Acta Pharmaceutica Sinica, 2021,56(7): 1832-1844. doi: 10.16438/j.0513-4870.2020-1944

FGFR4:一种有望治疗肝癌的靶点

FGFR4: a promising therapeutic target for liver cancer

  • 摘要: 成纤维细胞生长因子受体(fibroblast growth factor receptor,FGFR)作为受体酪氨酸激酶(receptor tyrosine kinases,RTKs)家族的成员,通过与配体成纤维细胞因子(fibroblast growth factors,FGFs)结合并激活下游信号通路参与多种生物学过程的调控,如细胞增殖、迁移、抗凋亡和血管生成等。FGFR基因扩增、错义突变、致癌融合引起的表达及调控异常与多种癌症发生发展有关,FGFR已成为癌症治疗中一个重要的潜在靶点。目前,这些研究大多集中在FGFR1~3上,然而越来越多的证据表明,FGFR4在多种肿瘤的发生和抗肿瘤耐药性的治疗中发挥着重要而独特的作用。FGF19-FGFR4信号通路的异常已被证实是肝癌的致癌因素。多个FGFR4选择性抑制剂已经进入临床试验,因此FGFR4是一种治疗FGF19-FGFR4信号异常导致的肝癌的有前途的靶点。本综述将重点介绍FGFR4在肝癌中的作用,包括对FGFR4的结构和配体、下游信号通路、在肝癌中的异常激活以及小分子FGFR4抑制剂、FGFR4单克隆抗体和联合免疫治疗的研究进展进行总结。

     

    Abstract: Fibroblast growth factor receptor (FGFR), as a member of the receptor tyrosine kinase family, participates in a variety of biological processes by binding to ligand fibroblast growth factors (FGFs) and activating downstream signaling pathways, such as cell proliferation, migration, anti-apoptosis, angiogenesis, etc. FGFR gene amplification, missense mutations, oncogenic fusion are related to the occurrence and development of many cancers. FGFR has become an important potential target in cancer treatment. At present most of these studies focus on FGFR1-3, however there is growing evidence implicating an important and unique role of FGFR4 in oncogenesis and resistance to anti-tumor therapy in multiple types of cancer. The abnormality of FGF19-FGFR4 signaling pathway has been proved to be a carcinogenic factor of liver cancer. Importantly, there are several novel FGFR4-specific inhibitors in clinical trials, FGFR4 is therefore a promising target for the treatment of hepatocellular carcinoma harboring aberrant FGF19-FGFR4 signaling. In this review, we focus on assessing the role of FGFR4 in liver cancer, including a summary of the structure and ligand of FGFR4, downstream signaling pathways, abnormal activation in liver cancer, and the research progress of small molecule FGFR4 inhibitors, FGFR4 monoclonal antibodies and combined immunotherapy.

     

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