FGF19 and its analog Aldafermin cooperate with MYC to induce aggressive hepatocarcinogenesis

• Published in: EMBO molecular medicine 2024-02, Vol.16 (2), p.238-250
• Main Authors: Ursic-Bedoya, José, Desandré, Guillaume, Chavey, Carine, Marie, Pauline, Polizzi, Arnaud, Rivière, Benjamin, Guillou, Hervé, Assenat, Eric, Hibner, Urszula, Gregoire, Damien
• Format: Article
• Language: English
• Subjects: Aldafermin (NGM282); Animals; Biomedical and Life Sciences; Biomedicine; Cancer; Carcinoma, Hepatocellular / drug therapy; Carcinoma, Hepatocellular / genetics; Carcinoma, Hepatocellular / metabolism; EMBO03; EMBO12; EMBO21; FGF19-15; Fibroblast Growth Factors / genetics; Fibroblast Growth Factors / metabolism; Hormones; Humans; Hydrodynamic Injections; Life Sciences; Liver Cancer; Liver Neoplasms / drug therapy; Liver Neoplasms / metabolism; Mice; Molecular Medicine; Oncogenic Cooperation
• ISSN: 1757-4684; 1757-4676; 1757-4684
• DOI: 10.1038/s44321-023-00021-x

FGF19 hormone has pleiotropic metabolic functions, including the modulation of insulin sensitivity, glucose/lipid metabolism and energy homeostasis. On top of its physiological metabolic role, FGF19 has been identified as a potentially targetable oncogenic driver, notably in hepatocellular carcinoma (HCC). Nevertheless, FGF19 remained an attractive candidate for treatment of metabolic disease, prompting the development of analogs uncoupling its metabolic and tumor-promoting activities. Using pre-clinical mice models of somatic mutation driven HCC, we assessed the oncogenicity of FGF19 in combination with frequent HCC tumorigenic alterations: p53 inactivation, CTNNB1 mutation, CCND1 or MYC overexpression. Our data revealed a strong oncogenic cooperation between FGF19 and MYC. Most importantly, we show that this oncogenic synergy is conserved with a FGF19-analog Aldafermin (NGM282), designed to solely mimic the hormone’s metabolic functions. In particular, even a short systemic treatment with recombinant proteins triggered rapid appearance of proliferative foci of MYC-expressing hepatocytes. The fact that FGF19 analog Aldafermin is not fully devoid of the hormone’s oncogenic properties raises concerns in the context of its potential use for patients with damaged, mutation-prone liver. Synopsis FGF19-analog Aldafermin, reportedly devoid of the hormone oncogenic properties, is envisioned as a therapeutic tool for the treatment of chronic liver diseases. Using pre-clinical mouse models, we found that FGF19 and Aldafermin cooperate with oncogenes implicated in liver carcinogenesis. FGF19/FGF15 cooperate with MYC, giving rise to aggressive, fast-growing tumors. Aldafermin retains oncogenic properties in the context of MYC overexpression. The hormone and its analog promote carcinogenesis through deregulation of identical pathways. FGF19-analog Aldafermin, reportedly devoid of the hormone oncogenic properties, is envisioned as a therapeutic tool for the treatment of chronic liver diseases. Using pre-clinical mouse models, we found that FGF19 and Aldafermin cooperate with oncogenes implicated in liver carcinogenesis.