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Review
. 2019 Jan 9;8(1):31.
doi: 10.3390/cells8010031.

Fibroblast Growth Factor Receptor 4 Targeting in Cancer: New Insights into Mechanisms and Therapeutic Strategies

Liwei Lang  1 , Yong Teng  2   3   4
Affiliations
Review

Fibroblast Growth Factor Receptor 4 Targeting in Cancer: New Insights into Mechanisms and Therapeutic Strategies

Liwei Lang et al. Cells. .

Abstract

Fibroblast growth factor receptor 4 (FGFR4), a tyrosine kinase receptor for FGFs, is involved in diverse cellular processes, including the regulation of cell proliferation, differentiation, migration, metabolism, and bile acid biosynthesis. High activation of FGFR4 is strongly associated with the amplification of its specific ligand FGF19 in many types of solid tumors and hematologic malignancies, where it acts as an oncogene driving the cancer development and progression. Currently, the development and therapeutic evaluation of FGFR4-specific inhibitors, such as BLU9931 and H3B-6527, in animal models and cancer patients, are paving the way to suppress hyperactive FGFR4 signaling in cancer. This comprehensive review not only covers the recent discoveries in understanding FGFR4 regulation and function in cancer, but also reveals the therapeutic implications and applications regarding emerging anti-FGFR4 agents. Our aim is to pinpoint the potential of FGFR4 as a therapeutic target and identify new avenues for advancing future research in the field.

Keywords: FGF19; FGFR4; anticancer; cancer signaling; gene regulation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The molecular structure of FGFR4. (A) The illustration of FGFR4 with mRNA structure. The transcript variant 1 of FGFR4 contains 18 exons and encodes isoform 1 of FGFR4 protein with the main function domains. (B) The main domains of FGFR4 with the corresponding function.
Figure 2
Figure 2
The FGF/FGFR4 signal axis. The signal transduction mediated by the FGF/FGFR4 axis is extremely complex, which includes PKC, ERK1/2, AKT, Src, and GSK3β signaling cascades. The homodimer of FGFR4 forms when binding to either canonical FGF subfamily members (FGF1, FGF2, FGF4, FGF6, FGF7, FGF8, FGF9, FGF16, FGF17, and FGF18) or FGF19 subfamily members (FGF19, FGF21, and FGF23). Heparin or heparin sulfate is required for the binding of canonical FGF subfamily members to FGFR4, whereas KLB acts as a co-receptor of FGFR4 to facilitate FGFR4 interacting with FGF19 subfamily members. When FGFR4 forms protein complexes with FGFs, it can be phosphorylated on three main tyrosine residues: Y642, Y643, and Y764.
Figure 3
Figure 3
The signal transduction cascades of FGF19/FGFR4 in cancer development and progression. In cancer cells, once FGFR4 receives the extracellular signal from FGF19, it activates many downstream pathways, including PI3K-AKT, MEK-ERK, and GSK3β-β-catenin, leading to increased tumor-promoting activities. FGFR4 activation can be blocked by two non-genetic strategies, using either monoclonal antibodies (e.g., U3-1798) or selective small-molecule inhibitors (e.g., BLU9931, H3B-6527 and FGF401).
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