title: Targeting FGFR4 inhibits hepatocellular carcinoma in preclinical mouse models.
abstract: The fibroblast growth factor (FGF)-FGF receptor (FGFR) signaling system plays critical roles in a variety of normal developmental and physiological processes. It is also well documented that dysregulation of FGF-FGFR signaling may have important roles in tumor development and progression. The FGFR4-FGF19 signaling axis has been implicated in the development of hepatocellular carcinomas (HCCs) in mice, and potentially in humans. In this study, we demonstrate that FGFR4 is required for hepatocarcinogenesis; the progeny of FGF19 transgenic mice, which have previously been shown to develop HCCs, bred with FGFR4 knockout mice fail to develop liver tumors. To further test the importance of FGFR4 in HCC, we developed a blocking anti-FGFR4 monoclonal antibody (LD1). LD1 inhibited: 1) FGF1 and FGF19 binding to FGFR4, 2) FGFR4-mediated signaling, colony formation, and proliferation in vitro, and 3) tumor growth in a preclinical model of liver cancer in vivo. Finally, we show that FGFR4 expression is elevated in several types of cancer, including liver cancer, as compared to normal tissues. These findings suggest a modulatory role for FGFR4 in the development and progression of hepatocellular carcinoma and that FGFR4 may be an important and novel therapeutic target in treating this disease.
authors.affiliation: Department of Pathology, Genentech, Inc, South San Francisco, California, United States of America.
authors.forename: Dorothy M
authors.initials: DM
authors.lastname: French
authors.forename: Benjamin C
authors.initials: BC
authors.lastname: Lin
authors.forename: Manping
authors.initials: M
authors.lastname: Wang
authors.forename: Camellia
authors.initials: C
authors.lastname: Adams
authors.forename: Theresa
authors.initials: T
authors.lastname: Shek
authors.forename: Kathy
authors.initials: K
authors.lastname: Hötzel
authors.forename: Brad
authors.initials: B
authors.lastname: Bolon
authors.forename: Ronald
authors.initials: R
authors.lastname: Ferrando
authors.forename: Craig
authors.initials: C
authors.lastname: Blackmore
authors.forename: Kurt
authors.initials: K
authors.lastname: Schroeder
authors.forename: Luis A
authors.initials: LA
authors.lastname: Rodriguez
authors.forename: Maria
authors.initials: M
authors.lastname: Hristopoulos
authors.forename: Rayna
authors.initials: R
authors.lastname: Venook
authors.forename: Avi
authors.initials: A
authors.lastname: Ashkenazi
authors.forename: Luc R
authors.initials: LR
authors.lastname: Desnoyers
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000517:prevention & control*; D002455:Cell Division; D004195:Disease Models, Animal; D008113:Liver Neoplasms / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics* / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; C496372:Fgfr4 protein, mouse; D051499:Receptor, Fibroblast Growth Factor, Type 4