Abstract
Fibroblast growth factor (FGF) receptor 4 (FGFR4) belongs to a family of tyrosine kinase receptor. FGFR4 is highly activated in certain types of cancer and its activation is closely associated with its specific ligand, FGF19. Indeed, FGF19-FGFR4 signaling is implicated in many cellular processes including cell proliferation, migration, metabolism, and differentiation. Since active FGF19-FGFR4 signaling acts as an oncogenic pathway in certain types of cancer, the development and therapeutic evaluation of FGFR4-specific inhibitors in cancer patients is a topic of significant interest. In this review, we aim to provide an updated overview of currently-available FGFR4 inhibitors and their ongoing clinical trials, as well as upcoming potential therapeutics. Further, we examined the possibility of enhancing the therapeutic efficiency of FGFR4 inhibitors in cancer patients. We also discussed the underlying molecular mechanisms of oncogenic activation of FGFR4 by FGF19.
Highlights
The fibroblast growth factor receptors (FGFRs) consist of four highly conserved transmembrane receptor tyrosine kinases (FGFR1-4) (Lin and Desnoyers, 2012)
FGFR4 expression was significantly upregulated in most liver cancer cases, and enhanced FGF19-FGFR4 signaling is linked to hepatocellular carcinoma (HCC) progression, metastasis, and poor survival (Sawey et al, 2011)
FGFR4 and FGF19 expressions were significantly associated with phosphorylated AKT expression, suggesting that FGFR4 might be a therapeutic target for these patients (Jaakkola et al, 1993; Penault-Llorca et al, 1995; Tiong et al, 2016)
Summary
The fibroblast growth factor receptors (FGFRs) consist of four highly conserved transmembrane receptor tyrosine kinases (FGFR1-4) (Lin and Desnoyers, 2012). FGFR4 expression was significantly upregulated in most liver cancer cases, and enhanced FGF19-FGFR4 signaling is linked to HCC progression, metastasis, and poor survival (Sawey et al, 2011). The FGF19-FGFR4 pathway enhances GSK3β-βcatenin signaling, inducing EMT and resulting in increased HCC metastasis (Goetz and Mohammadi, 2013; Zhao H. et al, 2016). The FGFR4 Arg388-variant enhances STAT3 signaling, promotes tumor progression, and is associated with poor prognosis of multiple cancers (Ulaganathan et al, 2015; Kogan et al, 2018). Accumulating evidences suggested that FGFR4-Arg388 allele was frequently seen in rapid tumor progression, increased metastasis and advanced stage of patients with breast, prostate, colon and lung cancer (Heinzle et al, 2014). It has been reported that the activation of FGF19-FGFR4 signaling is important in multiple tyrosine kinase inhibitor (TKI), sorafenib resistance for the treatment of HCC
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