Therapeutic targeting of FGF19-driven cancers with FGF21 variants

摘要 肝癌是美国增长最快的癌症。肝细胞癌（HCC）， 最常见的原发性肝癌类型，治疗选择有限，约占所有肝癌的75%。 每年有30,000人死于癌症。尽管最近FDA批准了几种用于治疗 晚期肝癌，HCC患者的五年生存率仍然保持在20%左右，突出了 需要开发更好的治疗方案。成纤维细胞生长因子19（FGF 19）的异常表达 最近被确定为HCC患者亚组中的致癌驱动因素。FGF 19是一种回肠来源的 肠因子属于内分泌成纤维细胞生长因子（FGF）家族，其通常作为一种免疫调节剂发挥作用。 内分泌激素和信号通过FGF受体（FGFR）途径在存在专性受体，β- 克洛索然而，肝脏中FGF 19的过表达通过FGF 19-FGFR 4促进不受控制的增殖。 β-Klotho通路以自分泌-旁分泌方式。我们以前的研究表明β-Klotho识别 FGF 19以与其识别FGF 21相同的方式被激活，FGF 21是内分泌FGF家族的另一个成员，不具有促有丝分裂活性。 β-Klotho与FGF 21或FGF 19之间的分子相互作用发生在相同的位置， 接口.基于我们对FGF 19和FGF 21的细胞信号传导机制的理解，我们假设 具有增强的对β-Klotho的结合亲和力的FGF 21变体将能够有效地与FGF 19竞争， 并因此抑制癌症中的异常FGF 19信号传导。本提案的目的是解决这一问题。 通过（1）使用生物物理学、生物化学和生物化学方法对FGF 21变体进行深入分析， 结构研究，（2）测试它们抑制FGF 19信号传导和阻断FGF 19驱动的细胞增殖的能力， 和（3）检查FGF 21变体克服/预防对激酶抑制剂的抗性的能力 目前在临床试验中。我们的研究结果将提供更深层次的机制和生物学 了解癌症中的FGF 19信号传导，并提供预防和治疗FGF 19驱动的癌症的新方法。

ABSTRACT Liver cancer is the most rapidly increasing cancer in the United States. Hepatocellular carcinoma (HCC), the most common type of primary liver cancer with limited treatment options, accounts for about 75% of all liver cancer and 30,000 deaths per year. Despite recent FDA approval of several new drugs for the treatment of advanced liver cancer, five-year survival rate for HCC patients still remains to be around 20 percent, highlighting the need to develop better therapeutic options. Aberrant expression of Fibroblast Growth Factor 19 (FGF19) has been recently identified as an oncogenic driver in a subset of HCC patients. FGF19 is an ileum-derived enterokine that belongs to endocrine Fibroblast Growth Factor (FGF) family, which normally functions as an endocrine hormone and signals though FGF receptor (FGFR) pathway in the presence of obligate receptor, β- Klotho. Overexpression of FGF19 in liver, however, promotes uncontrolled proliferation through FGF19-FGFR4- β-Klotho pathway in an autocrine-paracrine manner. Our previous studies revealed that β-Klotho recognizes FGF19 in the same manner as it recognizes FGF21, another member of endocrine FGF family with no mitogenic properties, and that the molecular interactions between β-Klotho and FGF21 or FGF19 occur at the identical interface. Based on our mechanistic understanding of cellular signaling by FGF19 and FGF21, we hypothesize that FGF21 variants with enhanced binding affinities to β-Klotho will be able to effectively compete with FGF19 and consequently inhibit aberrant FGF19 signaling in cancers. The aims of this proposal seek to address this overall hypothesis by (1) performing in-depth analyses of FGF21 variants using biophysical, biochemical, and structural studies, (2) testing their capacity to inhibit FGF19 signaling and block proliferation of FGF19-driven cancers, and (3) examining the abilities of FGF21 variants to overcome/prevent the resistance to kinase inhibitors currently in clinical trials. The outcome of our studies will provide deeper mechanistic and biological understanding of FGF19 signaling in cancers and offer novel means to prevent and treat FGF19-driven cancers.