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

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Fibroblast Growth Factor Receptor 4 Targeting in Cancer: New Insights Into Mechanisms and Therapeutic Strategies † cells Review Fibroblast Growth Factor Receptor 4 Targeting in Cancer: New Insights into Mechanisms and Therapeutic Strategies † Liwei Lang 1 and Yong Teng 1,2,3,* 1 Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA; [email protected] 2 Georgia Cancer Center, Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA 3 Department of Medical Laboratory, Imaging and Radiologic Sciences, College of Allied Health, Augusta University, Augusta, GA 30912, USA * Correspondence: [email protected]; Tel: +1-706-446-5611; Fax: +1-706-721-9415 † Running Title: Targeting FGFR4 for cancer therapy. Received: 30 November 2018; Accepted: 8 January 2019; Published: 9 January 2019 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: FGFR4; FGF19; gene regulation; cancer signaling; anticancer 1. Introduction Fibroblast growth factor receptors (FGFRs) have been found to play a vital role in tumorigenesis and cancer progression through increased cell proliferation, metastasis, and survival [1,2]. Compared with the other three FGFR family members, the signaling pathways and mechanisms of FGFR4 involved in cancer development are less characterized. The expression of FGFR4 is strictly regulated in human adult organs and tissues after fetal development, suggesting it perhaps has a particular relevance to tissue functions. Recently, elevated FGFR4 has been tightly correlated with cancer development and progression, making it an attractive target to develop novel and effective anticancer therapeutics. More efforts have been focused on developing selective inhibitors to target FGFR4, which show particular promise as an anticancer monotherapy or an adjunct treatment. 2. Molecular Characters of FGFR4 and Its Ligands 2.1. The Molecular Structure of FGFR4 FGFR4 is one of four family members harboring tyrosine kinase (TK) domains. The human FGFR4 gene is located on the long arm of chromosome 5 (5q 35.1). The FGFR4 gene consists of 18 exons Cells 2019, 8, 31; doi:10.3390/cells8010031 www.mdpi.com/journal/cells Cells 2019, 8, x 2 of 13 2. Molecular Characters of FGFR4 and Its Ligands 2.1. The Molecular Structure of FGFR4 Cells 2019, 8, 31 2 of 13 FGFR4 is one of four family members harboring tyrosine kinase (TK) domains. The human FGFR4 gene is located on the long arm of chromosome 5 (5q 35.1). The FGFR4 gene consists of 18 andexons has and five has transcript five transcript variants variants with three with ofthree them of them encoding encoding the FGFR4 the FGFR4 isoform isoform 1 (Figure 1 (Figure1A) [1A)3]. The[3]. 802The amino 802 amino acid (aa)acid core (aa) regioncore region in the in FGFR4 the FGFR4 protein protein contains contains four parts, four signalparts, peptidesignal peptide (1–21 aa), (1– extracellular21 aa), extracellular region (22–369region aa),(22–369 transmembrane aa), transmembrane region (70–390region (70–390 aa), and aa), the and intracellular the intracellular region (391–802region (391–802 aa) (Figure aa)1 (FigureB). Similar 1B). to Similar the other to the three othe FGFRr three members, FGFR members, the extracellular the extracellular region of region FGFR4 of consistsFGFR4 consists of three immunoglobulin-likeof three immunoglobulin-like domains domain (IgI, IgII,s (IgI, and IgII, IgIII), and which IgIII), are which essential are essential for specific for ligand-binding.specific ligand-binding. IgI is located IgI is in located 50–107 in aa 50–107 with a aa length with ofa length 97 aa. IgIIof 97 and aa. IgIIIIgII and are locatedIgIII are in located order in in 157–241order in aa 157–241 and 264–351 aa and aa.264–351 Compared aa. Compared with the with other the three other family three members, family members, FGFR4 doesFGFR4 not does have not a splicehave varianta splice onvariant the IgIII on the [4]. IgIII Several [4]. ligandSeveral binding ligand sitesbinding have sites been have identified, been identified, such as 273, such 278–280, as 273, 309–310,278–280, 316,309–310, and 337316, aa. and The 337 TK aa. domainsThe TK domains locate in locate the C terminalin the C terminal from 454–767 from aa454–767 with severalaa with tyrosineseveral tyrosine (Y) for autocatalysis, (Y) for autocatalysis, such as Y642, such Y643,as Y642, and Y643, Y764 and (Figure Y7642 ).(Figure 2). FigureFigure 1. 1.The The molecularmolecular structure structure of of FGFR4. FGFR4. ( A(A)) The The illustration illustration of of FGFR4 FGFR4 with with mRNA mRNA structure. structure. The The transcripttranscript variant variant 1 of1 of FGFR4 FGFR4 contains contains 18 exons18 exons and and encodes encodes isoform isoform 1 of FGFR41 of FGFR4 protein protein with the with main the functionmain function domains. domains. (B) The (B main) The domains main domains of FGFR4 of FGFR4 with the with corresponding the corresponding function. function. 2.2.2.2. TheThe LigandsLigands ofof FGFR4FGFR4 FGFsFGFs are are a a family family of of 2222 differentdifferent proteins proteins in in vertebrates vertebrates and and are are classified classified into into seven seven subfamilies subfamilies includingincluding FGF1,FGF1, FGF4, FGF7, FGF7, FGF8, FGF8, FGF9, FGF9, FGF19 FGF19 ligand ligand subfamily, subfamily, and and FGF11 FGF11 subfamily subfamily [5]. The [5]. Themembers members of FGF11 of FGF11 subfamily subfamily are not are ligands not ligands of FGFRs of FGFRs and are and known are known as FGF as homologous FGF homologous factors factors[5], while [5], all while other all six other subfamilies six subfamilies work as work ligands as ligands to bind to with bind FGFR4 with FGFR4 (Figure (Figure 2) [6]. 2In)[ other6]. In words, other words,ten canonical ten canonical FGF subfamily FGF subfamily members members (FGF1, (FGF1,FGF2, FGF4, FGF2, FGF6, FGF4, FGF7, FGF6, FGF8, FGF7, FGF9, FGF8, FGF16, FGF9, FGF16,FGF17, FGF17,and FGF18) and FGF18)and three and FGF19 three subfamily FGF19 subfamily members members(FGF19, FGF21, (FGF19, and FGF21, FGF23) and have FGF23) the potential have the to potentialbind FGFR4 to bind (Figure FGFR4 2). Canonical (Figure2). CanonicalFGFs bind FGFsto and bind activate to and FGFR4 activate with FGFR4 heparin/heparin with heparin/heparin sulfate (HS) β sulfate[7], while (HS) FGF19 [7], while subfamily FGF19 members subfamily need members β-klotho need (KLB)-klotho as a co-receptor (KLB) as ato co-receptor bind with FGFR4. to bind FGF1, with FGFR4.FGF4, and FGF1, FGF8, FGF4, have and a higher FGF8, affinity have ato higher bind FG affinityFR4 than to bind other FGFR4 canonical than FGFs. other Most canonical importantly, FGFs. MostFGF19, importantly, as an endocrine FGF19, asligand, an endocrine has a more ligand, specific has a selective more specific affinity selective to FGFR4 affinity than to FGFR4other FGFR than othermembers FGFR [8,9]. members [8,9]. Cells 2019, 8Cells, 31 2019, 8, x 3 of 13 3 of 13 Figure 2. The FGF/FGFR4 signal axis. The signal transduction mediated by the FGF/FGFR4 axis Figure 2. The FGF/FGFR4 signal axis. The signal transduction mediated by the FGF/FGFR4 axis is β is extremelyextremely complex, complex, which which includes includes PKC, ERK1/2, ERK1/2, AKT, AKT, Src, and Src, GSK3 andβ GSK3 signalingsignaling cascades. The cascades. The homodimerhomodimer of of FGFR4 FGFR4 forms forms when when binding binding to either to either canonical canonical FGF subfamily FGF subfamily members (FGF1, members FGF2, (FGF1, FGF2, FGF4,FGF4, FGF6, FGF6, FGF7, FGF8, FGF8, FGF9, FGF9, FGF16, FGF16, FGF17, FGF17, and FGF18) and or FGF18) FGF19 orsubfamily FGF19 members subfamily (FGF19, members (FGF19, FGF21,FGF21, and and FGF23). FGF23). Heparin Heparin or heparin or sulfate heparin is re sulfatequired for is the required binding of for canonical the binding FGF subfamily of canonical FGF subfamilymembers members to FGFR4, to whereas FGFR4, KLB whereas acts as a KLBco-recep actstor as of aFGFR4 co-receptor to facilitate of FGFR4FGFR4 interacting to facilitate with FGFR4 FGF19 subfamily members. When FGFR4 forms protein complexes with FGFs, it can be interacting with FGF19 subfamily members. When FGFR4 forms protein complexes with FGFs, it can phosphorylated on three main tyrosine residues: Y642, Y643, and Y764. be phosphorylated on three main tyrosine residues: Y642, Y643, and Y764. 2.3. The Physiologic Functions of FGFR4 2.3. The Physiologic Functions of FGFR4 As an important mediator of homeostasis in the liver, FGFR4 function is required for the As anmaintenance important of
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