FGF19–FGFR4 Signaling in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the sixth most common type of cancer, with an increasing mortality rate. Aberrant expression of fibroblast growth factor 19–fibroblast growth factor receptor 4 (FGF19–FGFR4) is reported to be an oncogenic-driver pathway for HCC patients. Thus, the FGF19–FGFR4 signaling pathway is a promising target for the treatment of HCC. Several pan-FGFR (1–4) and FGFR4-specific inhibitors are in different phases of clinical trials. In this review, we summarize the information, recent developments, binding modes, selectivity, and clinical trial phases of different available FGFR4/pan-FGF inhibitors. We also discuss future perspectives and highlight the points that should be addressed to improve the efficacy of these inhibitors.

Dissecting the Role of the FGF19-FGFR4 Signaling Pathway in Cancer Development and Progression

“…The FGFR4 gene has five transcript variants with three of them encoding the FGFR4 isoform 1 with 802 amino acids. The estimated molecular weight of FGFR4 isoform 1 is around 95-110 kDa, depending on its glycosylation levels (Raja et al, 2019). The basic protein domain structure of the FGFR4 is composed of four parts including a signaling peptide, three extracellular immunoglobulin (Ig) domains, a transmembrane domain, and an intracellular tyrosine kinase domain (Figure 1A).…”

“…Klotho interacts with FGFR4 forming 1:1 heterocomplex to facilitate binding between FGF19 and FGFR4. Later FGF19 binds to heterocomplex of Klotho and FGFR4 to form homodimer receptor complex, activating downstream signaling pathways Lang and Teng, 2019;Raja et al, 2019). Here, we summarized and discussed four main signaling pathways downstream of FGF19-FGFR4 signaling including Ras-Raf-MAPK, PI3K-AKT, epithelial-mesenchymal transition (EMT), and the signal transducer and activator of transcription (STAT) pathway (Figure 1A).…”

Activation of extracellular signal‐regulated kinase is associated with hepatocellular carcinoma with aggressive phenotypes

“…Therefore, other pathways besides the HGF/c‐MET axis might be associated with ERK phosphorylation. FGF19 and VEGFA are known to be associated with ERK phosphorylation . Huh7 and Hep3B cells, which express relatively low levels of c‐MET, but high levels of FGFR4, were reported not to be affected by c‐Met inhibitor treatment .…”

“…FGF19 and VEGFA are known to be associated with ERK phosphorylation. 44,45 Huh7 and Hep3B cells, which express relatively low levels of c-MET, but high levels of FGFR4, [46][47][48] were reported not to be affected by c-Met inhibitor treatment. 48 Together with findings in these studies and the present study, it was suggested that HCC cells might be highly dependent on specific signaling pathways for ERK phosphorylation.…”

Gene Therapy for Liver Cancers: Current Status from Basic to Clinics

“…Recent development in the field of molecular targeted agent (MTA) has shed light on chemotherapy for HCC [12] with the consideration of the molecular expression differences in the tumor. However, these MTAs also have limitations owing to the heterogeneity of HCC, and signaling pathway-specific inhibitors, such as those inhibiting fibroblast growth factor (FGF) 19-FGFR4 signaling pathways, are used in clinical trials [13]. Immune checkpoint inhibitors have also been tested [14], but have shown low efficacy in HCC as a current strategy, and further modification of the immune environment is essential [15][16][17].…”