Desnoyers L R, Pai R, Ferrando R E, Hötzel K, Le T, Ross J, Carano R, D'Souza A, Qing J, Mohtashemi I, Ashkenazi A, French D M
1Department of Molecular Oncology, Genentech Inc., South San Francisco, CA, USA.
Oncogene. 2008 Jan 3;27(1):85-97. doi: 10.1038/sj.onc.1210623. Epub 2007 Jun 25.
Although fibroblast growth factor 19 (FGF19) can promote liver carcinogenesis in mice its involvement in human cancer is not well characterized. Here we report that FGF19 and its cognate receptor FGF receptor 4 (FGFR4) are coexpressed in primary human liver, lung and colon tumors and in a subset of human colon cancer cell lines. To test the importance of FGF19 for tumor growth, we developed an anti-FGF19 monoclonal antibody that selectively blocks the interaction of FGF19 with FGFR4. This antibody abolished FGF19-mediated activity in vitro and inhibited growth of colon tumor xenografts in vivo and effectively prevented hepatocellular carcinomas in FGF19 transgenic mice. The efficacy of the antibody in these models was linked to inhibition of FGF19-dependent activation of FGFR4, FRS2, ERK and beta-catenin. These findings suggest that the inactivation of FGF19 could be beneficial for the treatment of colon cancer, liver cancer and other malignancies involving interaction of FGF19 and FGFR4.
尽管成纤维细胞生长因子19（FGF19）可促进小鼠肝癌发生，但其在人类癌症中的作用尚未得到充分阐明。在此我们报告，FGF19及其同源受体成纤维细胞生长因子受体4（FGFR4）在原发性人类肝癌、肺癌和结肠癌组织以及部分人类结肠癌细胞系中共同表达。为了测试FGF19对肿瘤生长的重要性，我们研发了一种抗FGF19单克隆抗体，该抗体可选择性阻断FGF19与FGFR4的相互作用。这种抗体在体外消除了FGF19介导的活性，在体内抑制了结肠肿瘤异种移植物的生长，并有效预防了FGF19转基因小鼠的肝细胞癌。该抗体在这些模型中的疗效与抑制FGF19依赖的FGFR4、FRS2、ERK和β-连环蛋白的激活有关。这些发现表明，FGF19失活可能有益于结肠癌、肝癌及其他涉及FGF19与FGFR4相互作用的恶性肿瘤的治疗。
