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，治疗选择有限，约占所有肝脏的75% 每年有30,000人死于癌症。尽管FDA最近批准了几种治疗糖尿病的新药 晚期肝癌患者的五年生存率仍保持在20%左右，凸显 需要开发更好的治疗方案。成纤维细胞生长因子19的异常表达 最近在部分肝细胞癌患者中被确定为致癌驱动因素。FGF19是一种来源于回肠的 肠因子属于内分泌成纤维细胞生长因子家族，通常作为一种 专性受体β存在下的内分泌激素和通过成纤维细胞生长因子受体的信号转导途径 克洛索。然而，在肝脏中过表达的FGF19通过FGF19-FGFR4促进了不受控制的增殖。 β-Klotho途径以自分泌-旁分泌的方式进行。我们之前的研究表明，β-Klotho认识到 FGF19识别FGF21的方式与识别FGF21的方式相同，FGF21是内分泌成纤维细胞生长因子家族的另一个成员，没有丝裂原 β-Klotho与FGF21或FGF19之间的分子相互作用发生在相同的 界面。基于我们对FGF19和FGF21细胞信号机制的理解，我们假设 与β-Klotho结合亲和力增强的FGF21变体将能够有效地与FGF19竞争 从而抑制癌症中异常的FGF19信号。这项提案的目的就是要解决这一问题 整体假设：(1)使用生物物理、生化和 结构研究，(2)检测它们抑制FGF19信号和阻断FGF19驱动的增殖的能力 癌症，以及(3)检测FGF21变异体克服/预防对激酶抑制剂的耐药性的能力 目前正在进行临床试验。我们的研究结果将提供更深层次的机制和生物学 了解FGF19在癌症中的信号转导，并为预防和治疗FGF19驱动的癌症提供新的手段。

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.