Alvarez-Sola Gloria, Uriarte Iker, Latasa M Ujue, Urtasun Raquel, Bárcena-Varela Marina, Elizalde Maria, Jiménez Maddalen, Rodriguez-Ortigosa Carlos M, Corrales Fernando J, Fernández-Barrena Maite G, Berasain Carmen, Avila Matías A
CIBERehd, University Clinic Navarra, Instituto de Salud Carlos III, Pamplona, Spain.
Dig Dis. 2017;35(3):158-165. doi: 10.1159/000450905. Epub 2017 Mar 1.
Advanced hepatocellular carcinoma (HCC) is a neoplastic disease with a very bad prognosis and increasing worldwide incidence. HCCs are resistant to conventional chemotherapy and the multikinase inhibitor sorafenib is the only agent that has shown some clinical efficacy. It is therefore important to identify key molecular mechanisms driving hepatocarcinogenesis for the development of more efficacious therapies. However, HCCs are heterogeneous tumors and different molecular subclasses have been characterized. This heterogeneity may underlie the poor performance of most of the targeted therapies so far tested in HCC patients. The fibroblast growth factor 15/19 (FGF15/19), FGF receptor 4 (FGFR4) and beta-Klotho (KLB) correceptor signaling system, a key regulator of bile acids (BA) synthesis and intermediary metabolism, is emerging as an important player in hepatocarcinogenesis. Key Messages: Aberrant signaling through the FGF15/19-FGFR4 pathway participates in the neoplastic behavior of HCC cells, promotes HCC development in mice and its overexpression has been characterized in a subset of HCC tumors from patients with poorer prognosis. Pharmacological interference with FGF15/19-FGFR4 signaling inhibits experimental hepatocarcinogenesis, and specific FGFR4 inhibitors are currently being tested in selected HCC patients with tumoral FGF19-FGFR4/KLB expression.
Interference with FGF19-FGFR4 signaling represents a novel strategy in HCC therapy. Selection of candidate patients based on tumoral FGF19-FGFR4/KLB levels as biomarkers may result in increased efficacy of FGFR4-targeted drugs. Nevertheless, attention should be paid to the potential on target toxic effects of FGFR4 inhibitors due to the key role of this signaling system in BA metabolism.
晚期肝细胞癌（HCC）是一种预后极差且全球发病率不断上升的肿瘤性疾病。HCC对传统化疗耐药，多激酶抑制剂索拉非尼是唯一显示出一定临床疗效的药物。因此，识别驱动肝癌发生的关键分子机制对于开发更有效的治疗方法至关重要。然而，HCC是异质性肿瘤，已鉴定出不同的分子亚类。这种异质性可能是迄今为止在HCC患者中测试的大多数靶向治疗效果不佳的原因。成纤维细胞生长因子15/19（FGF15/19）、FGF受体4（FGFR4）和β-klotho（KLB）共受体信号系统是胆汁酸（BA）合成和中间代谢的关键调节因子，正在成为肝癌发生中的重要参与者。关键信息：通过FGF15/19-FGFR4途径的异常信号传导参与HCC细胞的肿瘤行为，促进小鼠肝癌发展，并且在预后较差患者的一部分HCC肿瘤中其表达上调。对FGF15/19-FGFR4信号传导的药理学干扰可抑制实验性肝癌发生，目前正在对选定的肿瘤FGF19-FGFR4/KLB表达的HCC患者测试特异性FGFR4抑制剂。
干扰FGF19-FGFR4信号传导是HCC治疗的一种新策略。基于肿瘤FGF19-FGFR4/KLB水平作为生物标志物选择候选患者可能会提高FGFR4靶向药物的疗效。然而，由于该信号系统在BA代谢中的关键作用，应注意FGFR4抑制剂的潜在靶上毒性作用。
