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Dark and bright side of targeting fibroblast growth factor receptor 4 in the liver

  • Raffaella Maria Gadaleta
    Affiliations
    Department of Interdisciplinary Medicine, University of Bari, Piazza Giulio Cesare 11, 70100 Bari Italy
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  • Antonio Moschetta
    Correspondence
    Corresponding author. Address: Clinica Medica “Cesare Frugoni,” Department of Interdisciplinary Medicine, University of Bari “Aldo Moro,” Piazza Giulio Cesare 11, 70124 Bari, Italy. Tel.: 0805592767, fax: (39) 0805555388.
    Affiliations
    Department of Interdisciplinary Medicine, University of Bari, Piazza Giulio Cesare 11, 70100 Bari Italy
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Published:August 05, 2021DOI:https://doi.org/10.1016/j.jhep.2021.07.029

      Summary

      Fibroblast growth factor (FGF) receptor 4 (FGFR4) and its cognate ligand, FGF19, are implicated in a range of cellular processes, including differentiation, metabolism and proliferation. Indeed, their aberrant activation has been associated with the development of hepatic tumours. Despite great advances in early diagnosis and the development of new therapies, liver cancer is still associated with a high mortality rate, owing primarily to high molecular heterogeneity and unclear molecular targeting. The development of FGFR4 inhibitors is a promising tool in patients with concomitant supraphysiological levels of FGF19 and several clinical trials are testing these treatments for patients with advanced hepatocellular carcinoma (HCC). Conversely, using FGF19 analogues to activate FGFR4-KLOTHO β represents a novel therapeutic strategy in patients presenting with cholestatic liver disorders and non-alcoholic steatohepatitis, which could potentially prevent the development of metabolic HCC. Herein, we provide an overview of the currently available therapeutic options for targeting FGFR4 in HCC and other liver diseases, highlighting the need to carefully stratify patients and personalise therapeutic strategies.

      Keywords

      Fibroblast growth factor receptor 4 and fibroblast growth factor 19: Structure and function

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      • Postel-Vinay S.
      • Andre F.
      • Soria J.C.
      Targeting FGFR signaling in cancer.
      and signal transducer and activator of transcription 3 (STAT3).
      • Calvisi D.F.
      • Ladu S.
      • Gorden A.
      • Farina M.
      • Conner E.A.
      • Lee J.S.
      • et al.
      Ubiquitous activation of Ras and Jak/Stat pathways in human HCC.
      ,
      • Feng D.Y.
      • Zheng H.
      • Tan Y.
      • Cheng R.X.
      Effect of phosphorylation of MAPK and Stat3 and expression of c-fos and c-jun proteins on hepatocarcinogenesis and their clinical significance.
      • He G.
      • Yu G.Y.
      • Temkin V.
      • Ogata H.
      • Kuntzen C.
      • Sakurai T.
      • et al.
      Hepatocyte IKKbeta/NF-kappaB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation.
      • Jiang R.
      • Tan Z.
      • Deng L.
      • Chen Y.
      • Xia Y.
      • Gao Y.
      • et al.
      Interleukin-22 promotes human hepatocellular carcinoma by activation of STAT3.
      • Liang C.
      • Xu Y.
      • Ge H.
      • Li G.
      • Wu J.
      Clinicopathological significance and prognostic role of p-STAT3 in patients with hepatocellular carcinoma.
      Moreover, aberrant activation of FGF19-FGFR4 has also been shown to boost the metastatic potential of HCC via GSK3β-β-catenin signalling.
      • Goetz R.
      • Mohammadi M.
      Exploring mechanisms of FGF signalling through the lens of structural biology.
      ,
      • Zhao H.
      • Lv F.
      • Liang G.
      • Huang X.
      • Wu G.
      • Zhang W.
      • et al.
      FGF19 promotes epithelial-mesenchymal transition in hepatocellular carcinoma cells by modulating the GSK3beta/beta- catenin signaling cascade via FGFR4 activation.
      Observational data have shown that FGFR4 and FGF19 are co-expressed in primary human liver tumours
      • Desnoyers L.R.
      • Pai R.
      • Ferrando R.E.
      • Hotzel K.
      • Le T.
      • Ross J.
      • et al.
      Targeting FGF19 inhibits tumor growth in colon cancer xenograft and FGF19 transgenic hepatocellular carcinoma models.
      and FGF19 is overexpressed in HCC samples compared to non-tumour tissue and seems to be an independent negative prognostic factor for survival.
      • Miura S.
      • Mitsuhashi N.
      • Shimizu H.
      • Kimura F.
      • Yoshidome H.
      • Otsuka M.
      • et al.
      Fibroblast growth factor 19 expression correlates with tumor progression and poorer prognosis of hepatocellular carcinoma.
      ,
      • Zhao H.
      • Lv F.
      • Liang G.
      • Huang X.
      • Wu G.
      • Zhang W.
      • et al.
      FGF19 promotes epithelial-mesenchymal transition in hepatocellular carcinoma cells by modulating the GSK3beta/beta- catenin signaling cascade via FGFR4 activation.
      ,
      • Hyeon J.
      • Ahn S.
      • Lee J.J.
      • Song D.H.
      • Park C.K.
      Expression of fibroblast growth factor 19 is associated with recurrence and poor prognosis of hepatocellular carcinoma.
      ,
      • Zhou M.
      • Yang H.
      • Learned R.M.
      • Tian H.
      • Ling L.
      Non-cell-autonomous activation of IL-6/STAT3 signaling mediates FGF19-driven hepatocarcinogenesis.
      Moreover, FGF19 amplification has been observed at advanced stages in aggressive HCC tumours.
      • Schulze K.
      • Imbeaud S.
      • Letouze E.
      • Alexandrov L.B.
      • Calderaro J.
      • Rebouissou S.
      • et al.
      Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets.
      Circulating FGF19 levels are also increased in patients with HCC compared to controls and are reduced after surgical resection.
      • Miura S.
      • Mitsuhashi N.
      • Shimizu H.
      • Kimura F.
      • Yoshidome H.
      • Otsuka M.
      • et al.
      Fibroblast growth factor 19 expression correlates with tumor progression and poorer prognosis of hepatocellular carcinoma.
      Also, in a methylome study, FGF19 was hypermethylated in HCC compared to adjacent peritumoral tissue,
      • Ye C.
      • Tao R.
      • Cao Q.
      • Zhu D.
      • Wang Y.
      • Wang J.
      • et al.
      Whole-genome DNA methylation and hydroxymethylation profiling for HBV-related hepatocellular carcinoma.
      although further analysis is warranted based on the very small sample size of this and other clinical studies linking FGF19 to HCC development. Pre-clinical investigations have greatly helped in delineating the role of FGF19 and its interaction with FGFR4 in the onset and development of HCC. Paralleling clinical data, animal models strongly suggest that FGFR4 acquires its oncogenic capabilities in the presence of supraphysiological levels of FGF19. The effect of FGF19 on hepatocyte growth and proliferation was originally identified from the phenotypic observation that FGF19 transgenic mice developed invasive tumours between 10 and 12 months of age and acute FGF19 administration also increases hepatocellular proliferation.
      • Nicholes K.
      • Guillet S.
      • Tomlinson E.
      • Hillan K.
      • Wright B.
      • Frantz G.D.
      • et al.
      A mouse model of hepatocellular carcinoma: ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice.
      Furthermore, FGF19-adenoviral administration induced hepatocarcinogenesis with different latency depending on the genetic background of the model under consideration.
      • Zhou M.
      • Wang X.
      • Phung V.
      • Lindhout D.A.
      • Mondal K.
      • Hsu J.Y.
      • et al.
      Separating tumorigenicity from bile acid regulatory activity for endocrine hormone FGF19.
      In vivo and in vitro studies have shown that FGF19 administration causes hepatic induction of several molecules implicated in proliferative mechanisms, such as the transforming growth factor-β, annexin a2, vigiline, vascular cell adhesion molecule 1
      • Massafra V.
      • Milona A.
      • Vos H.R.
      • Burgering B.M.
      • van Mil S.W.
      Quantitative liver proteomics identifies FGF19 targets that couple metabolism and proliferation.
      and the epidermal growth factor amphiregulin. The latter induces Cyclin D1
      • Latasa M.U.
      • Salis F.
      • Urtasun R.
      • Garcia-Irigoyen O.
      • Elizalde M.
      • Uriarte I.
      • et al.
      Regulation of amphiregulin gene expression by beta-catenin signaling in human hepatocellular carcinoma cells: a novel crosstalk between FGF19 and the EGFR system.
      while being negatively associated with E-cadherin expression in HCC tissue, thereby promoting the epithelial-mesenchymal transition via GSK3-β catenin.
      • Miura S.
      • Mitsuhashi N.
      • Shimizu H.
      • Kimura F.
      • Yoshidome H.
      • Otsuka M.
      • et al.
      Fibroblast growth factor 19 expression correlates with tumor progression and poorer prognosis of hepatocellular carcinoma.
      ,
      • Zhao H.
      • Lv F.
      • Liang G.
      • Huang X.
      • Wu G.
      • Zhang W.
      • et al.
      FGF19 promotes epithelial-mesenchymal transition in hepatocellular carcinoma cells by modulating the GSK3beta/beta- catenin signaling cascade via FGFR4 activation.
      This, in turn, contributes to resistance to apoptosis.
      • Teng Y.
      • Zhao H.
      • Gao L.
      • Zhang W.
      • Shull A.Y.
      • Shay C.
      FGF19 protects hepatocellular carcinoma cells against endoplasmic reticulum stress via activation of FGFR4-GSK3beta-Nrf2 signaling.
      Corroborating these findings, strategies aimed at diminishing the oncogenic potential of FGFR4-FGF19, such as RNA interference, small hairpin RNA or neutralising monoclonal antibodies against FGF19
      • Sawey E.T.
      • Chanrion M.
      • Cai C.
      • Wu G.
      • Zhang J.
      • Zender L.
      • et al.
      Identification of a therapeutic strategy targeting amplified FGF19 in liver cancer by Oncogenomic screening.
      ,
      • Desnoyers L.R.
      • Pai R.
      • Ferrando R.E.
      • Hotzel K.
      • Le T.
      • Ross J.
      • et al.
      Targeting FGF19 inhibits tumor growth in colon cancer xenograft and FGF19 transgenic hepatocellular carcinoma models.
      ,
      • Elzi D.J.
      • Song M.
      • Blackman B.
      • Weintraub S.T.
      • Lopez-Terrada D.
      • Chen Y.
      • et al.
      FGF19 functions as autocrine growth factor for hepatoblastoma.
      prevented hepatocarcinogenesis, as did FGFR4 loss of function.
      • French D.M.
      • Lin B.C.
      • Wang M.
      • Adams C.
      • Shek T.
      • Hotzel K.
      • et al.
      Targeting FGFR4 inhibits hepatocellular carcinoma in preclinical mouse models.
      Additionally, a small clinical study has shown that a copy number gain for FGF19 may be a predictor of the response to the multikinase inhibitor sorafenib.
      • Kaibori M.
      • Sakai K.
      • Ishizaki M.
      • Matsushima H.
      • De Velasco M.A.
      • Matsui K.
      • et al.
      Increased FGF19 copy number is frequently detected in hepatocellular carcinoma with a complete response after sorafenib treatment.
      Another pre-clinical study has shown the antitumor activity of BLU9931, a small irreversible FGFR4 inhibitor, in mice bearing xenografts with amplified FGF19 expression.
      • Hagel M.
      • Miduturu C.
      • Sheets M.
      • Rubin N.
      • Weng W.
      • Stransky N.
      • et al.
      First selective small molecule inhibitor of FGFR4 for the treatment of hepatocellular carcinomas with an activated FGFR4 signaling pathway.
      BLU9931 has also been shown to counteract FGF19-dependent resistance to sorafenib.
      • Gao L.
      • Shay C.
      • Lv F.
      • Wang X.
      • Teng Y.
      Implications of FGF19 on sorafenib-mediated nitric oxide production in hepatocellular carcinoma cells - a short report.
      Nevertheless, caution should be taken in translating results obtained in rodent models to humans. Despite Fgf15 and FGF19 being considered orthologues, they display a certain level of divergence in their tissue expression and biological action, complicating the translation of mouse data to humans. Moreover, FGFRs’ tissue specificity and the presence of KLB represent additional layers of complexity. Although both ileal Fgf15 and FGF19 are well established to repress hepatic BA synthesis after binding to FGFR4–KLB, the regulation of systemic metabolism and tumorigenic activity by the 2 orthologues appear to be different [reviewed in
      • Gadaleta R.M.
      • Moschetta A.
      Metabolic Messengers: fibroblast growth factor 15/19.
      ]. In fact, while prolonged FGF19 exposure causes hepatic tumorigenesis in db/db,
      • Hansen A.M.K.
      • Vienberg S.G.
      • Lykkegaard K.
      • Zhao X.
      • Tingqing G.
      • Han D.
      • et al.
      Differential receptor selectivity of the FGF15/FGF19 orthologues determines distinct metabolic activities in db/db mice.
      ,
      • Zhou M.
      • Luo J.
      • Chen M.
      • Yang H.
      • Learned R.M.
      • DePaoli A.M.
      • et al.
      Mouse species-specific control of hepatocarcinogenesis and metabolism by FGF19/FGF15.
      diet-induced obese
      • Zhou M.
      • Luo J.
      • Chen M.
      • Yang H.
      • Learned R.M.
      • DePaoli A.M.
      • et al.
      Mouse species-specific control of hepatocarcinogenesis and metabolism by FGF19/FGF15.
      and Mdr2-knockout
      • Xie M.H.
      • Holcomb I.
      • Deuel B.
      • Dowd P.
      • Huang A.
      • Vagts A.
      • et al.
      FGF-19, a novel fibroblast growth factor with unique specificity for FGFR4.
      ,
      • Zhou M.
      • Learned R.M.
      • Rossi S.J.
      • DePaoli A.M.
      • Tian H.
      • Ling L.
      Engineered fibroblast growth factor 19 reduces liver injury and resolves sclerosing cholangitis in Mdr2-deficient mice.
      mice, and in transgenic mice ectopically expressing FGF19,
      • Nicholes K.
      • Guillet S.
      • Tomlinson E.
      • Hillan K.
      • Wright B.
      • Frantz G.D.
      • et al.
      A mouse model of hepatocellular carcinoma: ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice.
      Fgf15 does not appear to be pro-tumorigenic.
      • Xie M.H.
      • Holcomb I.
      • Deuel B.
      • Dowd P.
      • Huang A.
      • Vagts A.
      • et al.
      FGF-19, a novel fibroblast growth factor with unique specificity for FGFR4.
      Whereas pharmacological activation of FXR in both humans and rodents does not seem to prime hepatic tumorigenesis, the precise relationship between Fgf15 and its specific activation of other FGFRs could possibly explain why species-specific molecular players do not affect proliferative control.
      • Gadaleta R.M.
      • Moschetta A.
      Metabolic Messengers: fibroblast growth factor 15/19.
      Several specific and non-specific FGFR4 inhibitors (the latter pan-inhibiting other FGF receptors) have shown promising results in the treatment of advanced HCC.
      Given the prominent metabolic role of FGF19, especially in modulating bile acid synthesis, pool size and composition, indiscriminate inhibition of FGFR4 carries safety risks and can cause liver toxicity.

      Therapeutic targeting of FGFR4 in HCC: The bright side

      Despite the great advances in early diagnosis and the development of new therapies, HCC is still associated with a high mortality rate because of high molecular heterogeneity and unclear molecular targeting. Furthermore, highly variable gene mutations impact HCC aetiology in different patients and intratumoural molecular heterogeneity adds a further layer of complexity, often confounding the outcome of biopsy examinations. In recent years, several molecular-targeted drugs have been developed and hold promise for the treatment of patients with HCC. Therapies aimed at inhibiting FGFR4 and FGF19 are thought to be promising for the therapeutic management of HCC, although not in all cases. In this paragraph, we will examine current clinical strategies targeting FGFR4-FGF19. Several FGFR inhibitors are under development and in different phases of clinical trials for several types of malignancy, including HCC (Table 1). While the vast majority of these drugs are kinase inhibitors, other molecules with inhibitory properties are also being studied (e.g. antibodies, antisense inhibitory molecules, ligand traps) and are either in clinical trials for other conditions or in a pre-clinical stage of development.
      Table 1Therapeutic inhibition of FGFRs in hepatocellular carcinoma and other cancers.
      CompanyDrugTherapeutic indicationTargetTrial phaseClinical trial number
      Principia BiopharmaPRN1371Solid tumoursFGFRs pan inhibitorINCT02608125
      AstellasASP5878Solid tumoursFGFRs pan inhibitorINCT02038673
      Eli LillyLY2874455Advanced & metastatic cancerFGFRs pan inhibitorIINCT01212107
      AstraZenecaAZD4547Advanced refractory cancers/lymphomas/multiple myelomaFGFRs pan inhibitorIINTC04439240
      NovartisInfigratinibTumours with FGFRs genetic alterationsFGFRs pan inhibitorINCT02160041
      NovartisInfigratinibAdvanced cholangiocarcinomaFGFRs pan inhibitorIINCT02150967
      JanssenErdafitinibAdvanced hepatocellular carcinomaFGFRs pan inhibitorIINCT02421185
      NovartisFGF401Hepatocellular carcinomaFGFR4 specific inhibitorIINCT02325739
      H3 Biomedics IncH3B-6527Advanced hepatocellular carcinomaFGFR4 specific inhibitorIINCT02834780
      Blueprint Medicine Corp.Fisogatinib (BLU-554)Hepatocellular carcinomaFGFR4 specific inhibitorI/IINCT02508467, NCT04194801
      FGFR, fibroblast growth factor receptor.

      Pan-FGFR inhibitors

      Two drugs are currently in phase I: PRN1371 (Principia Biofarma, NCT02608125) and ASP5878 (Astellas, NCT02038673). These 2 molecules have been developed to target FGFRs in solid tumours. The inhibitory action of the irreversible covalent FGFR1-4 kinase inhibitor PRN1371 has been reported in HCC, gastric and lung cancer
      • Brameld K.A.
      • Owens T.D.
      • Verner E.
      • Venetsanakos E.
      • Bradshaw J.M.
      • Phan V.T.
      • et al.
      Discovery of the irreversible covalent FGFR inhibitor 8-(3-(4-Acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(me thylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (PRN1371) for the treatment of solid tumors.
      and the selective small-molecule inhibitor ASP5878 suppresses the growth of a range of HCC cell lines expressing FGF19, induces tumour regression in xenograft models and improves the efficacy of sorafenib.
      • Futami T.
      • Okada H.
      • Kihara R.
      • Kawase T.
      • Nakayama A.
      • Suzuki T.
      • et al.
      ASP5878, a novel inhibitor of FGFR1, 2, 3, and 4, inhibits the growth of FGF19-expressing hepatocellular carcinoma.
      In addition, there are 4 pan-FGFR inhibitors in phase II clinical trials: LY2874455 (Eli Lilly, NCT01212107), AZD4547 (AstraZeneca, NCT02038673), infigratinib (Novartis, NCT02150967), and erdafitinib (Janssen, NCT02421185).
      The small kinase inhibitor LY2874455 is not an HCC drug, but it has been described as promising after demonstrating strong inhibition of FGFRs in other advanced and metastatic cancers, such as myelomas, lung, colorectal, and gastric cancers.
      • Michael M.
      • Bang Y.J.
      • Park Y.S.
      • Kang Y.K.
      • Kim T.M.
      • Hamid O.
      • et al.
      A phase 1 study of LY2874455, an oral selective pan-FGFR inhibitor, in patients with advanced cancer.
      The tyrosine kinase inhibitor AZD4547 has been described as a good inhibitor of FGFRs in a small phase I study of a Japanese cohort with advanced solid malignancies (e.g. lung, colorectal, breast, and others). However, despite showing a good efficacy against FGFR,
      • Partanen J.
      • Makela T.P.
      • Eerola E.
      • Korhonen J.
      • Hirvonen H.
      • Claesson-Welsh L.
      • et al.
      FGFR-4, a novel acidic fibroblast growth factor receptor with a distinct expression pattern.
      • Mohammadi M.
      • Olsen S.K.
      • Ibrahimi O.A.
      Structural basis for fibroblast growth factor receptor activation.
      • Klint P.
      • Claesson-Welsh L.
      Signal transduction by fibroblast growth factor receptors.
      it displayed a weaker activity against FGFR4.
      • Saka H.
      • Kitagawa C.
      • Kogure Y.
      • Takahashi Y.
      • Fujikawa K.
      • Sagawa T.
      • et al.
      Safety, tolerability and pharmacokinetics of the fibroblast growth factor receptor inhibitor AZD4547 in Japanese patients with advanced solid tumours: a Phase I study.
      It is currently in phase II for advanced refractory cancers/lymphomas/multiple myeloma (NTC04439240).
      A phase I study evaluating the receptor tyrosine kinase inhibitor infigratinib for tumours with alterations in FGFR has recently been completed (NCT02160041). As for AZD4547, infigratinib shows a good efficacy against FGFR1-3, and a weaker one against FGFR4.
      • Guagnano V.
      • Furet P.
      • Spanka C.
      • Bordas V.
      • Le D.M.
      • Stamm C.
      • et al.
      Discovery of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamin o]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase.
      ,
      • Guagnano V.
      • Kauffmann A.
      • Wohrle S.
      • Stamm C.
      • Ito M.
      • Barys L.
      • et al.
      FGFR genetic alterations predict for sensitivity to NVP-BGJ398, a selective pan-FGFR inhibitor.
      Cancer cell lines with a gain of FGF19 copy number, coupled with a proportional increase in KLB, are sensitive to infigratinib.
      • Guagnano V.
      • Kauffmann A.
      • Wohrle S.
      • Stamm C.
      • Ito M.
      • Barys L.
      • et al.
      FGFR genetic alterations predict for sensitivity to NVP-BGJ398, a selective pan-FGFR inhibitor.
      It is currently in phase II clinical trials for patients with advanced cholangiocarcinoma (NCT02150967) and it showed an effective response against FGFR signalling pathways in HCC.
      • Huynh H.
      • Lee L.Y.
      • Goh K.Y.
      • Ong R.
      • Hao H.X.
      • Huang A.
      • et al.
      Infigratinib mediates vascular normalization, impairs metastasis, and improves chemotherapy in hepatocellular carcinoma.
      However, it is not part of any FDA-approved clinical trials for HCC.
      A dysfunctional bile acid pool promotes liver fibrosis, currently contributing to a significant shift in the aetiology of HCC from viral hepatitis to metabolic disease.
      Finally, the small kinase inhibitor erdafitinib (Balversa, JNJ-42756493) is a pan-FGFR
      • Partanen J.
      • Makela T.P.
      • Eerola E.
      • Korhonen J.
      • Hirvonen H.
      • Claesson-Welsh L.
      • et al.
      FGFR-4, a novel acidic fibroblast growth factor receptor with a distinct expression pattern.
      • Mohammadi M.
      • Olsen S.K.
      • Ibrahimi O.A.
      Structural basis for fibroblast growth factor receptor activation.
      • Klint P.
      • Claesson-Welsh L.
      Signal transduction by fibroblast growth factor receptors.
      • Zhang X.
      • Ibrahimi O.A.
      • Olsen S.K.
      • Umemori H.
      • Mohammadi M.
      • Ornitz D.M.
      Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family.
      inhibitor for which a phase II clinical trial in advanced HCC has just been completed. Erdafitinib has shown target inhibition and pathway modulation in FGFR pathway-activated cellular models of HCC and other cancers and in pre-clinical mouse xenograft models of FGFR-driven hepatocellular and other solid tumours.
      • Nishina T.
      • Takahashi S.
      • Iwasawa R.
      • Noguchi H.
      • Aoki M.
      • Doi T.
      Safety, pharmacokinetic, and pharmacodynamics of erdafitinib, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, in patients with advanced or refractory solid tumors.
      Recently, erdafitinib has been approved by the FDA for the treatment of locally advanced or metastatic FGFR2- or FGFR3-positive urothelial carcinoma.
      • Markham A.
      Erdafitinib: first global approval.

      FGFR4-specific inhibitors in HCC

      While trials are clinically evaluating the action of pan-FGFR inhibitors for a number of conditions, their very low specificity towards FGFR4 potentially limits their efficacy in HCC.
      • Packer L.M.
      • Pollock P.M.
      Paralog-specific kinase inhibition of FGFR4: adding to the arsenal of anti-FGFR agents.
      In addition, on target FGFR1-3-mediated dose-limiting toxicities, such as soft tissue mineralisation and hyperphosphatemia – that often cause treatment interruption and dose reduction with consequent loss of efficacy – are major drawbacks that could limit FGFR4 potency.
      • Packer L.M.
      • Pollock P.M.
      Paralog-specific kinase inhibition of FGFR4: adding to the arsenal of anti-FGFR agents.
      For these reasons, a number of FGFR4-specific inhibitors are currently under investigation for the treatment of hepatic tumours.
      The reversible-covalent inhibitor FGF401 (Novartis, NCT02325739) specifically targets FGFR4 in patients with HCC. FGF401 has a remarkable antitumor activity in mice bearing HCC tumour xenografts and patient-derived xenograft models that are positive for FGF19, FGFR4, and KLB.
      • Huynh H.
      • Prawira A.
      • Le T.B.U.
      • Vu T.C.
      • Hao H.X.
      • Huang A.
      • et al.
      FGF401 and vinorelbine synergistically mediate antitumor activity and vascular normalization in FGF19-dependent hepatocellular carcinoma.
      ,
      • Weiss A.
      • Adler F.
      • Buhles A.
      • Stamm C.
      • Fairhurst R.A.
      • Kiffe M.
      • et al.
      FGF401, A first-in-class highly selective and potent FGFR4 inhibitor for the treatment of FGF19-driven hepatocellular cancer.
      FGF401 was the first FGFR4 inhibitor to enter clinical trials, and a phase II study has recently been completed for HCC and other solid malignancies. Preliminary data suggested promising clinical activity and a manageable safety profile consistent with FGFR4 pathway inhibition.
      • Huynh H.
      • Prawira A.
      • Le T.B.U.
      • Vu T.C.
      • Hao H.X.
      • Huang A.
      • et al.
      FGF401 and vinorelbine synergistically mediate antitumor activity and vascular normalization in FGF19-dependent hepatocellular carcinoma.
      Pre-clinical studies have shown that the highly selective FGFR4 covalent inhibitor H3B-6527 (alone, or in combination with a CDK4/6 inhibitor) suppresses tumour growth in a xenograft model of HCC driven by aberrant activation of FGFR4-FGF19 and that FGF19 expression could be used as a predictive biomarker of response.
      • Joshi J.J.
      • Coffey H.
      • Corcoran E.
      • Tsai J.
      • Huang C.L.
      • Ichikawa K.
      • et al.
      H3B-6527 is a potent and selective inhibitor of FGFR4 in FGF19-driven hepatocellular carcinoma.
      Currently, H3B-6527 is being evaluated in a phase I study in patients with advanced HCC (H3 Biomedics Inc, NCT02834780).
      Fisogatinib (also known as BLU-554) is another small-molecule FGFR4 inhibitor currently being tested in phase I and phase II clinical trials in patients with HCC (NCT02508467, NCT04194801, respectively). Data indicate an acceptable toxicity profile with early evidence of antitumor activity in patients with FGF19-positive HCC.
      • Kim R.D.
      • Sarker D.
      • Meyer T.
      • Yau T.
      • Macarulla T.
      • Park J.W.
      • et al.
      First-in-Human phase I study of fisogatinib (BLU-554) validates aberrant FGF19 signaling as a driver event in hepatocellular carcinoma.

      Therapeutic targeting of FGFR4-FGF19 in HCC: Dark side and loose ends

      Preliminary results emerging from clinical trials on FGFR4 inhibitors are promising and the huge effort in this direction has definitely led to advances in the clinical management of HCC. However, this strategy is not successful in every clinical setting and the overall outcome of these therapies is currently not satisfactory. Given the prominent metabolic role of FGF19, indiscriminate inhibition of FGFR4 carries several intrinsic safety risks and can cause metabolic disruption, particularly concerning BA homeostasis. In fact, blocking FGFR4-FGF19 can cause liver toxicity and diarrhoea.
      • Pai R.
      • French D.
      • Ma N.
      • Hotzel K.
      • Plise E.
      • Salphati L.
      • et al.
      Antibody-mediated inhibition of fibroblast growth factor 19 results in increased bile acids synthesis and ileal malabsorption of bile acids in cynomolgus monkeys.
      Physicians should weigh the risk/benefit ratio of reaching a significant degree of blockage vs. therapeutic advantages achieved without inducing gastrointestinal, hepatic and metabolic toxicity caused by chronically elevated BA levels and enhanced enterohepatic circulation (resulting from the expression of ileal and hepatic BA transporters).
      • Mellor H.R.
      Targeted inhibition of the FGF19-FGFR4 pathway in hepatocellular carcinoma; translational safety considerations.
      Moreover, despite several experimental models relying on FGFR4 hyperactivation due to supraphysiological levels of FGF19, FGF19 amplification has only been assessed in 5% of patients with HCC and mostly occurs in association with cirrhosis, in patients previously infected with hepatitis B.
      • Ahn S.M.
      • Jang S.J.
      • Shim J.H.
      • Kim D.
      • Hong S.M.
      • Sung C.O.
      • et al.
      Genomic portrait of resectable hepatocellular carcinomas: implications of RB1 and FGF19 aberrations for patient stratification.
      In addition, proteogenomic analyses have suggested that somatic variants often display reduced protein abundance compared to germline variants and that, although copy number alterations strongly affect mRNA abundance, relatively few of these extend to the protein level.
      • Zhang B.
      • Wang J.
      • Wang X.
      • Zhu J.
      • Liu Q.
      • Shi Z.
      • et al.
      Proteogenomic characterization of human colon and rectal cancer.
      The infrequency of FGF19 amplification poses a challenge for the design and performance of clinical trials, since achieving statistical significance would require the screening of an extremely high number of patients,
      • Hagel M.
      • Miduturu C.
      • Sheets M.
      • Rubin N.
      • Weng W.
      • Stransky N.
      • et al.
      First selective small molecule inhibitor of FGFR4 for the treatment of hepatocellular carcinomas with an activated FGFR4 signaling pathway.
      and not only on a genomic level but also on a proteomic one. This also reflects the problem of the very low sample size used in many of the published studies, reinforcing the need for caution when extrapolating clinical data linking FGF19 to HCC. In addition, despite the anti-oncogenic properties of FGFR4-FGF19 blockage, one needs to consider the ability of FGF15/19 to play a role in liver regeneration and that FXR deficiency, resulting in loss of FGF15/19 production, is involved in the onset and development of HCC. Lastly, but equally importantly, a dysfunctional BA pool promotes liver fibrosis. Although the main risk factors for HCC are HBV and HCV infections, their relative contribution, especially in developed countries, is rapidly declining due to the effectiveness of HBV vaccines and anti-HCV drugs.
      • Chang M.H.
      • You S.L.
      • Chen C.J.
      • Liu C.J.
      • Lee C.M.
      • Lin S.M.
      • et al.
      Decreased incidence of hepatocellular carcinoma in hepatitis B vaccinees: a 20-year follow-up study.
      • Kimer N.
      • Dahl E.K.
      • Gluud L.L.
      • Krag A.
      Antiviral therapy for prevention of hepatocellular carcinoma in chronic hepatitis C: systematic review and meta-analysis of randomised controlled trials.
      • Kulik L.
      • El-Serag H.B.
      Epidemiology and management of hepatocellular carcinoma.
      This has caused an aetiopathogenetic shift of HCC onset and progression to a different background. Currently, severe liver fibrosis and cirrhosis are major risk factors for HCC, with up to 90% of cases occurring on the background of a cirrhotic liver.
      • Fattovich G.
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      • Donato F.
      Hepatocellular carcinoma in cirrhosis: incidence and risk factors.
      ,
      • O'Rourke J.M.
      • Sagar V.M.
      • Shah T.
      • Shetty S.
      Carcinogenesis on the background of liver fibrosis: implications for the management of hepatocellular cancer.
      HCC onset in the absence of fibrosis can be induced by hereditary metabolic conditions, such as porphyria, type-1 glycogen storage diseases and hemochromatosis, but is much less frequent.
      • O'Rourke J.M.
      • Sagar V.M.
      • Shah T.
      • Shetty S.
      Carcinogenesis on the background of liver fibrosis: implications for the management of hepatocellular cancer.
      ,
      • Trevisani F.
      • Frigerio M.
      • Santi V.
      • Grignaschi A.
      • Bernardi M.
      Hepatocellular carcinoma in non-cirrhotic liver: a reappraisal.
      Given safety concerns over the use of FGF19 therapeutics in terms of proliferative potential, therapeutic strategies have shifted to using newly generated FGF19 analogues that lack proliferative activities while maintaining metabolic ones.
      In order to increase therapeutic options for each patient, early diagnosis and molecular characterisation of liver cancer is one of the most pressing challenges.

      Liver regeneration

      In the context of liver regeneration, Fgf15 knockout mice display dysfunctionalities in cell cycle pathways that impair hepatocyte proliferation,
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      causing advanced liver damage, and even higher mortality (depending on mouse strain) after partial hepatectomy
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      Identification of fibroblast growth factor 15 as a novel mediator of liver regeneration and its application in the prevention of post-resection liver failure in mice.
      or acetaminophen overdose.
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      Fibroblast growth factor 15 deficiency increases susceptibility but does not improve repair to acetaminophen-induced liver injury in mice.
      These negative effects can be further worsened by chronically elevated levels of BAs
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      due to lack of control of their synthetic rate. In addition, knock-down of FGFR4 by short-interfering RNA causes liver necrosis in partially hepatectomised mice due to intrahepatic BA overload (228). Conversely, mouse models of partial hepatectomy or chemically induced liver damage have elegantly shown that the administration of Fgf15
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      or the FGF19/apolipoprotein A-1 chimera
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      promotes liver repair and reduces liver injury. In line with these findings, intestinal FXR reactivation in Fxr-knockout mice prevents the onset of HCC.
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      Prevention of spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice by intestinal-specific farnesoid X receptor reactivation.
      Also, in a mouse model of BA-induced spontaneous HCC due to the homozygous disruption of the phospholipid transporter Abcb4,
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      Mice with homozygous disruption of the mdr2 P-glycoprotein gene. A novel animal model for studies of nonsuppurative inflammatory cholangitis and hepatocarcinogenesis.
      long-term administration of a diet enriched with the FXR ligand INT-767 protects from hepatic tumorigenesis through Fgf15-dependent suppression of hepatic Cyp7a1.
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      Long-term administration of nuclear bile acid receptor FXR agonist prevents spontaneous hepatocarcinogenesis in Abcb4(-/-) mice.
      There is also recent evidence showing that BAs themselves could play a direct or indirect role in adjusting the liver size as physiologically needed, a phenomenon called hepatostat.
      • Alvarez-Sola G.
      • Uriarte I.
      • Latasa M.U.
      • Jimenez M.
      • Barcena-Varela M.
      • Santamaria E.
      • et al.
      Bile acids, FGF15/19 and liver regeneration: from mechanisms to clinical applications.
      ,
      • Naugler W.E.
      • Tarlow B.D.
      • Fedorov L.M.
      • Taylor M.
      • Pelz C.
      • Li B.
      • et al.
      Fibroblast growth factor signaling controls liver size in mice with humanized livers.
      In all these experimental contexts, regardless of the culprit (Fxr deficiency or FGFR4-FGF15/19 blockage), chronic BA overproduction in the context of diminished BA export capabilities and changes in BA composition cause an under-stimulation of FXR activity, resulting in a vicious cycle and ultimately worsening liver damage.
      Patient stratification and identification of patients at risk of developing metabolic HCC (e.g. patients with cholestasis, fibrosis, steatosis and NASH) will greatly advance personalisation of treatment.

      Metabolic diseases, fibrosis, NASH and HCC

      Alterations in BA pool size and composition promote the onset of hepatic, intestinal and metabolic diseases. In fact, decreased levels of FGF19 have been reported in human metabolic diseases, including type 2 diabetes and metabolic syndrome,
      • Barutcuoglu B.
      • Basol G.
      • Cakir Y.
      • Cetinkalp S.
      • Parildar Z.
      • Kabaroglu C.
      • et al.
      Fibroblast growth factor-19 levels in type 2 diabetic patients with metabolic syndrome.
      • Gerhard G.S.
      • Styer A.M.
      • Wood G.C.
      • Roesch S.L.
      • Petrick A.T.
      • Gabrielsen J.
      • et al.
      A role for fibroblast growth factor 19 and bile acids in diabetes remission after Roux-en-Y gastric bypass.
      • Sonne D.P.
      • van Nierop F.S.
      • Kulik W.
      • Soeters M.R.
      • Vilsboll T.
      • Knop F.K.
      Postprandial plasma concentrations of individual bile acids and FGF-19 in patients with type 2 diabetes.
      • Stejskal D.
      • Karpisek M.
      • Hanulova Z.
      • Stejskal P.
      Fibroblast growth factor-19: development, analytical characterization and clinical evaluation of a new ELISA test.
      and obesity.
      • Gallego-Escuredo J.M.
      • Gomez-Ambrosi J.
      • Catalan V.
      • Domingo P.
      • Giralt M.
      • Fruhbeck G.
      • et al.
      Opposite alterations in FGF21 and FGF19 levels and disturbed expression of the receptor machinery for endocrine FGFs in obese patients.
      • Gomez-Ambrosi J.
      • Gallego-Escuredo J.M.
      • Catalan V.
      • Rodriguez A.
      • Domingo P.
      • Moncada R.
      • et al.
      FGF19 and FGF21 serum concentrations in human obesity and type 2 diabetes behave differently after diet- or surgically-induced weight loss.
      • Mraz M.
      • Lacinova Z.
      • Kavalkova P.
      • Haluzikova D.
      • Trachta P.
      • Drapalova J.
      • et al.
      Serum concentrations of fibroblast growth factor 19 in patients with obesity and type 2 diabetes mellitus: the influence of acute hyperinsulinemia, very-low calorie diet and PPAR-alpha agonist treatment.
      • Renner O.
      • Harsch S.
      • Matysik S.
      • Lutjohann D.
      • Schmitz G.
      • Stange E.F.
      Upregulation of hepatic bile acid synthesis via fibroblast growth factor 19 is defective in gallstone disease but functional in overweight individuals.
      Additionally, altered BA signalling has been associated with the onset of cholestasis and liver fibrosis in patients with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NASH).
      • Eren F.
      • Kurt R.
      • Ermis F.
      • Atug O.
      • Imeryuz N.
      • Yilmaz Y.
      Preliminary evidence of a reduced serum level of fibroblast growth factor 19 in patients with biopsy-proven nonalcoholic fatty liver disease.
      ,
      • Jiao N.
      • Baker S.S.
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      • Liu W.
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      • et al.
      Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD.
      Particularly important in this context is NASH, a progressive form of fatty liver disease which is on the rise in Western countries, affecting more than 80 million people in the world and representing one of the most pressing and neglected diseases.
      • Sheka A.C.
      • Adeyi O.
      • Thompson J.
      • Hameed B.
      • Crawford P.A.
      • Ikramuddin S.
      Nonalcoholic steatohepatitis: a review.
      ,
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      • Tacke F.
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      Global perspectives on nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.
      NASH is a chronic disorder with unmet therapeutic needs and its incidence is predicted to increase significantly over the next decades.
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      Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease.
      NASH increases the risk of developing advanced liver disease and HCC. Poor dietary habits and associated obesity affect the onset and progression of NASH and, in patients with this condition, liver fibrosis and steatosis are the main determinants of mortality.
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      Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta-analysis.
      ,
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      • et al.
      Association between fibrosis stage and outcomes of patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis.
      In this context, emerging evidence indicates that maintaining a proper BA metabolism is critical to prevent liver inflammation and fibrosis, the primum movens of NASH progression into HCC. In fact, inappropriately high levels of BAs, particularly species with a more hydrophobic profile, have been shown to promote liver fibrosis.
      • Arab J.P.
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      • Dawson P.A.
      • Arrese M.
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      Bile acids and nonalcoholic fatty liver disease: molecular insights and therapeutic perspectives.
      Another important aspect to keep in mind is that, often, a lack of FGF19 reflects impaired FXR expression and/or activity and several pre-clinical and clinical studies have shown that promoting FGF19 activities by targeting FXR counteracts the development of cholestasis, fibrosis and NASH.
      • Degirolamo C.
      • Modica S.
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      • Morgano A.
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      • et al.
      Prevention of spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice by intestinal-specific farnesoid X receptor reactivation.
      ,
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      • Bellafante E.
      • Murzilli S.
      • Salvatore L.
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      • et al.
      Selective activation of nuclear bile acid receptor FXR in the intestine protects mice against cholestasis.
      ,
      • Neuschwander-Tetri B.A.
      • Loomba R.
      • Sanyal A.J.
      • Lavine J.E.
      • Van Natta M.L.
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      • et al.
      Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial.
      Because of the pro-mitogenic potential of FGF19 (via FGFR4), there has been concern regarding its use for clinical purposes. To overcome this problem, scientists have tried to uncover the connection between the molecular structure of FGF19 and the regulation of multiple metabolic and proliferative pathways via its binding to FGFR4. This effort resulted in the generation of novel FGF19 analogues, successfully engineered to maintain the typical FGF19 BA homeostasis/metabolic properties while lacking tumorigenic activities. The major difference between FGF19 analogues and wild-type FGF19 is in the amino-terminal part of the protein. For instance, the analogue M70, also known as NGM282 or Aldafermin (NGM Biopharmaceuticals), carries 3 amino acid substitutions (A30S, G31S, H33L) and a 5-amino acid deletion at the N-terminus, and is able to activate the ERK signalling pathway, ultimately inhibiting Cyp7a1 without concomitantly inducing STAT3-dependent proliferation.
      • Zhou M.
      • Wang X.
      • Phung V.
      • Lindhout D.A.
      • Mondal K.
      • Hsu J.Y.
      • et al.
      Separating tumorigenicity from bile acid regulatory activity for endocrine hormone FGF19.
      Mechanistically, in vitro and in vivo data have shown that wild-type FGF19 phosphorylates and activates STAT3-dependent induction of survivin, cyclin D1 and Bcl-X1. This oncogenic pathway is frequently dysregulated in HCC
      • He G.
      • Karin M.
      NF-kappaB and ST.
      : in fact, STAT3 has been found to be phosphorylated and activated in approximately 60% of HCCs
      • He G.
      • Yu G.Y.
      • Temkin V.
      • Ogata H.
      • Kuntzen C.
      • Sakurai T.
      • et al.
      Hepatocyte IKKbeta/NF-kappaB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation.
      and to correlate with poor prognosis in patients with HCC.
      • Calvisi D.F.
      • Ladu S.
      • Gorden A.
      • Farina M.
      • Conner E.A.
      • Lee J.S.
      • et al.
      Ubiquitous activation of Ras and Jak/Stat pathways in human HCC.
      STAT3 activation does not occur when M70 is used. As a result, adenoviral-mediated delivery of wild-type FGF19 induces hepatic cancer with different latency according to the examined strain, while mice treated with an adenovirus containing the FGF19 engineered variant M70 display no hepatic tumours, both macroscopically and microscopically, while showing preserved BA homeostasis.
      • Zhou M.
      • Wang X.
      • Phung V.
      • Lindhout D.A.
      • Mondal K.
      • Hsu J.Y.
      • et al.
      Separating tumorigenicity from bile acid regulatory activity for endocrine hormone FGF19.
      In line with this finding, FGF19-M70 protects mice from cholestatic liver injury.
      • Zhou M.
      • Learned R.M.
      • Rossi S.J.
      • DePaoli A.M.
      • Tian H.
      • Ling L.
      Engineered fibroblast growth factor 19 reduces liver injury and resolves sclerosing cholangitis in Mdr2-deficient mice.
      We have shown that another FGF19 analogue, namely FGF19-M52 (NGM Biopharmaceuticals) that differs from wild-type FGF19 by 5 amino acid substitutions (A30S, G31S, H33L, V34L, H35Q) and 5 amino acid deletions at the N-terminus, prevents tumorigenesis in 2 different models of BA-induced spontaneous hepatocarcinogenesis.
      • Gadaleta R.M.
      • Scialpi N.
      • Peres C.
      • Cariello M.
      • Ko B.
      • Luo J.
      • et al.
      Suppression of hepatic bile acid synthesis by a non-tumorigenic FGF19 analogue protects mice from fibrosis and hepatocarcinogenesis.
      This is achieved by FGF19-M52-dependent suppression of hepatic BA synthesis and modulation of the BA pool size and composition.
      • Gadaleta R.M.
      • Scialpi N.
      • Peres C.
      • Cariello M.
      • Ko B.
      • Luo J.
      • et al.
      Suppression of hepatic bile acid synthesis by a non-tumorigenic FGF19 analogue protects mice from fibrosis and hepatocarcinogenesis.
      On a translational level, FGF19-M70 reduces BA synthesis in humans
      • Luo J.
      • Ko B.
      • Elliott M.
      • Zhou M.
      • Lindhout D.A.
      • Phung V.
      • et al.
      A nontumorigenic variant of FGF19 treats cholestatic liver diseases.
      and has gone through phase I and II clinical trials for several conditions, displaying an acceptable safety profile (Table 2). In particular, it has been shown to decrease markers of liver damage, inflammation and fibrosis in cholestatic liver disorders,
      • Hirschfield G.M.
      • Chazouilleres O.
      • Drenth J.P.
      • Thorburn D.
      • Harrison S.A.
      • Landis C.S.
      • et al.
      Effect of NGM282, an FGF19 analogue, in primary sclerosing cholangitis: a multicenter, randomized, double-blind, placebo-controlled phase II trial.
      ,
      • Mayo M.J.
      • Wigg A.J.
      • Leggett B.A.
      • Arnold H.
      • Thompson A.J.
      • Weltman M.
      • et al.
      NGM282 for treatment of patients with primary biliary cholangitis: a multicenter, randomized, double-blind, placebo-controlled trial.
      which may contribute to the development of liver cancer. Additionally, a very recent phase II clinical study has shown that aldafermin reduces hepatic fat accumulation in patients with NASH in a phase II clinical trial.
      • Harrison S.A.
      • Rinella M.E.
      • Abdelmalek M.F.
      • Trotter J.F.
      • Paredes A.H.
      • Arnold H.L.
      • et al.
      NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.
      ,
      • Harrison S.A.
      • Neff G.
      • Guy C.D.
      • Bashir M.R.
      • Paredes A.H.
      • Frias J.P.
      • et al.
      Efficacy and safety of aldafermin, an engineered FGF19 analog, in a randomized, double-blind, placebo-controlled trial of patients with nonalcoholic steatohepatitis.
      Targeting dysmetabolic events in chronic liver disease represents an unexploited preventative and/or therapeutic opportunity for an increasing number of patients.
      Table 2Therapeutic activation of FGFR4 via the FGF19-engineered analogue NGM282 (aldafermin) in hepatic metabolic diseases.
      CompanyDrugTherapeutic indicationTargetTrial phaseClinical trial number
      NGM BiopharmaceuticalsNGM282Primary biliary cholangitisFGF19 analogue/biased FGFR4 activatorII/IIbNCT02026401, NCT02135536
      NGM BiopharmaceuticalsNGM282Primary sclerosing cholangitisFGF19 analogue/biased FGFR4 activatorIINCT02704364
      NGM BiopharmaceuticalsNGM282NASH and stage 2/3 liver fibrosisFGF19 analogue/biased FGFR4 activatorIIbNCT03912532
      NGM BiopharmaceuticalsNGM282NASHFGF19 analogue/biased FGFR4 activatorIINCT02443116
      NGM BiopharmaceuticalsNGM282Impaired hepatic function (Child-Pugh A, B, C)FGF19 analogue/biased FGFR4 activatorINCT04823702
      NGM BiopharmaceuticalsNGM282Compensated NASH cirrhosisFGF19 analogue/biased FGFR4 activatorIINCT04210245
      FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; NASH, non-alcoholic steatohepatitis.

      Conclusion

      In this review, we have discussed the latest advances in therapies blocking downstream signalling pathways of FGFR4 in the context of HCC. Despite the improvement in early HCC diagnosis due to the latest generation of diagnostic tools, survival is still low in patients affected by this disease. The human FGFR4-FGF19 axis plays a fascinating role in both development and metabolism and its targeting is considered extremely promising for the treatment of liver diseases and HCC. The heterogeneous molecular landscape of HCC is associated with unique metabolic dysregulations. Lessons from both humans and mice have shown that indiscriminate FGFR4 inhibition could result in severe metabolic derangements especially in patients who have metabolic comorbidities, which could potentially be not only therapeutically unsuccessful but also counterproductive. Conversely, hepatic conditions in dysmetabolic patients often progress to HCC. While it is evident that long-term abnormally high FGF19 levels could be pro-carcinogenic, at least in a subset of patients with HCC, this does not necessarily indicate that physiological or drug-induced production of FGF19, such as by FXR-activating drugs, necessarily elevates cancer risk. In fact, chronic FXR activation in different mouse models has not promoted fibrosis nor HCC development
      • Degirolamo C.
      • Modica S.
      • Vacca M.
      • Di T.G.
      • Morgano A.
      • D'Orazio A.
      • et al.
      Prevention of spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice by intestinal-specific farnesoid X receptor reactivation.
      ,
      • Cariello M.
      • Peres C.
      • Zerlotin R.
      • Porru E.
      • Sabba C.
      • Roda A.
      • et al.
      Long-term administration of nuclear bile acid receptor FXR agonist prevents spontaneous hepatocarcinogenesis in Abcb4(-/-) mice.
      and FXR-based therapies have not been shown to elevate the risk of HCC development in patients. Nevertheless, the long-term consequences of FXR-dependent transcriptional changes are uncertain and, although unlikely, potential tumorigenic risk should be monitored. The latest generation of engineered variants has demonstrated that FGF19 is a viable FGFR4-biased druggable option, and holds particular promise for gut-liver metabolic conditions that increase the risk of metabolic HCC, such as cholestatic liver diseases, namely primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), and, potentially, NASH. However, caution is imperative and further research is warranted. Extended clinical trials are awaited to interpret and tackle the long-term side effects of these therapies, especially related to increased serum cholesterol levels and LDL – currently successfully tackled by the concomitant use of statins
      • Rinella M.E.
      • Trotter J.F.
      • Abdelmalek M.F.
      • Paredes A.H.
      • Connelly M.A.
      • Jaros M.J.
      • et al.
      Rosuvastatin improves the FGF19 analogue NGM282-associated lipid changes in patients with non-alcoholic steatohepatitis.
      – and gastrointestinal symptoms, such as diarrhoea and increased transit time, that emerged in PSC and PBC trials.
      • Hirschfield G.M.
      • Chazouilleres O.
      • Drenth J.P.
      • Thorburn D.
      • Harrison S.A.
      • Landis C.S.
      • et al.
      Effect of NGM282, an FGF19 analogue, in primary sclerosing cholangitis: a multicenter, randomized, double-blind, placebo-controlled phase II trial.
      ,
      • Mayo M.J.
      • Wigg A.J.
      • Leggett B.A.
      • Arnold H.
      • Thompson A.J.
      • Weltman M.
      • et al.
      NGM282 for treatment of patients with primary biliary cholangitis: a multicenter, randomized, double-blind, placebo-controlled trial.
      To date, mutational profiling of clinical HCC tissues has guided the subgrouping of molecular subtypes of HCC.
      • Goossens N.
      • Sun X.
      • Hoshida Y.
      Molecular classification of hepatocellular carcinoma: potential therapeutic implications.
      There remain several challenges including overcoming the lack of access to HCC tissue specimens in clinical practice and expanding patient cohorts to investigate the mechanisms underlying the beneficial effects of targeting FGFR4. Moreover, early diagnosis and HCC molecular characterisation should attempt to identify and link genomic/proteomic aberrations with the tumour microenvironment and metabolic dysregulation. This would result in more effective therapeutic targeting, as has been shown for other type of tumours, like oestrogen receptor-positive breast cancer or HER2-positive gastric cancer. Personalisation of clinical treatments should be the focus of future research (Fig. 1). There is no one-size-fits-all therapy, especially in diseases like this, with a consistent pattern of metabolic comorbidities. On one hand, inhibiting FGFR4 could be a putative anticancer strategy in a small number of patients with specific molecular subtypes of HCC. On the other hand, targeting dysmetabolic activities in chronic liver diseases that progress to HCC represents an unexploited preventative and/or therapeutic opportunity in an expanding number of patients.
      Figure thumbnail gr1
      Fig. 1Personalised therapies in liver diseases and hepatocellular carcinoma.
      FGFR4-targetedinhibition in the presence of supraphysiological levels of FGF19 is showing promising results in patients with advanced liver cancer. On the other hand, the use of FGF19-based analogue activating only the FGFR4-dependent phosphorylation cascade aimed at reducing BA synthesis while unaffecting proliferative pathways has shown great results in cholestatic liver disorders, fibrosis and NASH, gaining positions as a potential treatment for metabolic HCC. BA, bile acid; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; HCC, hepatocellular carcinoma; NASH, non-alcoholic steatohepatitis.

      Abbreviations

      BA, bile acid; ERK, extracellular-signal-regulated kinase; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; FXR, farnesoid X receptor; GSK3, glycogen synthase kinase 3; HCC, hepatocellular carcinoma; KLB, β-Klotho; JNK, Jun N-terminal kinase; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis; STAT3, signal transducer and activator of transcription 3.

      Financial support

      A. Moschetta is funded by Italian Association for Cancer Research (AIRC) IG 2019-23139 , Miur-Prin 2017J3E2W2_002 and INNOMA Puglia FESR-FSE 2014-2020 n.4TCJLV4-POR.

      Authors’ contributions

      RMG and AM conceived the review outline, discussed and contributed to the manuscript. RMG interpreted the relevant literature and wrote the manuscript. AM supervised the work.

      Conflict of interest

      The authors have no conflicts of interest to declare and there is no financial interest to report.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following is the supplementary data to this article:

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