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Review
. 2019 Jun 4;8(6):536.
doi: 10.3390/cells8060536.

FGF19- FGFR4 Signaling in Hepatocellular Carcinoma

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Free PMC article
Review

FGF19- FGFR4 Signaling in Hepatocellular Carcinoma

Aroosha Raja et al. Cells. .
Free PMC article

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.

Keywords: FGF19; FGFR4; HCC; inhibitors; prognosis.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structural overview of fibroblast growth factor receptor 4 (FGFR4) protein.
Figure 2
Figure 2
The association of FGFR4 with different hallmarks of cancer, as reported in the literature. (Scales of bars from left to right represent the lowest to highest number of associations reported)
Figure 3
Figure 3
The association of FGF19 with different hallmarks of cancer, as reported in the literature. (Scales of bars from left to right represent the lowest to highest number of associations reported)
Figure 4
Figure 4
Interaction network of FGFR4 with different genes with high potency and functional similarity. The interaction network is based on various parameters including co-expression, genetic interactivity, shared protein domains, co-localization and physical interactions.
Figure 5
Figure 5
Involvement of FGFR4-related signaling pathways. Involvement in cell proliferation is depicted on the far left; next to it the cell survival signaling pathway is shown, and on the right side the cell migration pathway is explained (adapted from Atlas of Genetics and Cytogenetics in Oncology and Haematology).
Figure 6
Figure 6
Binding mechanism of FGF19 to FGFR4 leads to FRS2 along with recruitment of growth factor receptor-bound protein 2 (GRB2), ultimately leading to activation of the RasRafERK1/2 MAPK and PI3KAkt pathways.
Figure 7
Figure 7
Selected overview of pan-FGFRs and FGFR4-specific inhibitors in different stages of clinical trials for hepatocellular carcinoma (HCC).
Figure 8
Figure 8
(a) Structure of LY2874455, and (b) binding mode of LY2874455 with the FGFR4 kinase domain (PDB code 5JKG).
Figure 9
Figure 9
(a) Structure of JNJ-42756493 (b) Interaction of JNJ-42756493 with FGFR1 (PDB code 5EW8).

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