Fibroblast growth factor (FGF) family receptors act as homo- and heterodimers, and are characterized by Ig-like loops in the extracellular domain, in which disulphide bridges may form across protein partners to allow the formation of covalent dimers which may be constitutively active. FGF receptors have been implicated in achondroplasia, angiogenesis and numerous congenital disorders. At least 22 members of the FGF gene family have been identified in the human genome [11]. Within this group, subfamilies of FGF may be divided into canonical, intracellular and hormone-like FGFs. FGF1-FGF10 have been identified to act through FGF receptors, while FGF11-14 appear to signal through intracellular targets. Other family members are less well characterized [7].
Approved FGFR inhibitors include erdafitinib, pemigatinib, and futibatinib. Common adverse effects associated with these drugs, and approaches for their management are reviewed in [6].

Splice variation of the receptors can influence agonist responses. FGFRL1 (Q8N441) is a truncated kinase-null analogue.

Various antibodies and tyrosine kinase inhibitors have been developed against FGF receptors [3,10]. PD161570 is an FGFR tyrosine kinase inhibitor [1], while PD173074 has been described to inhibit FGFR1 and FGFR3 [5].

* Key recommended reading is highlighted with an asterisk

* Subbiah V, Verstovsek S. (2023) Clinical development and management of adverse events associated with FGFR inhibitors. Cell Rep Med, 4 (10): 101204. [PMID:37757826]

1. Batley BL, Doherty AM, Hamby JM, Lu GH, Keller P, Dahring TK, Hwang O, Crickard K, Panek RL. (1998) Inhibition of FGF-1 receptor tyrosine kinase activity by PD 161570, a new protein-tyrosine kinase inhibitor. Life Sci, 62 (2): 143-50. [PMID:9488112]

2. Hagel M, Miduturu C, Sheets M, Rubin N, Weng W, Stransky N, Bifulco N, Kim JL, Hodous B, Brooijmans N et al.. (2015) First Selective Small Molecule Inhibitor of FGFR4 for the Treatment of Hepatocellular Carcinomas with an Activated FGFR4 Signaling Pathway. Cancer Discov, 5 (4): 424-37. [PMID:25776529]

3. Liang G, Liu Z, Wu J, Cai Y, Li X. (2012) Anticancer molecules targeting fibroblast growth factor receptors. Trends Pharmacol Sci, 33 (10): 531-41. [PMID:22884522]

4. Ornitz DM, Xu J, Colvin JS, McEwen DG, MacArthur CA, Coulier F, Gao G, Goldfarb M. (1996) Receptor specificity of the fibroblast growth factor family. J Biol Chem, 271 (25): 15292-7. [PMID:8663044]

5. Skaper SD, Kee WJ, Facci L, Macdonald G, Doherty P, Walsh FS. (2000) The FGFR1 inhibitor PD 173074 selectively and potently antagonizes FGF-2 neurotrophic and neurotropic effects. J Neurochem, 75 (4): 1520-7. [PMID:10987832]

6. Subbiah V, Verstovsek S. (2023) Clinical development and management of adverse events associated with FGFR inhibitors. Cell Rep Med, 4 (10): 101204. [PMID:37757826]

7. Wesche J, Haglund K, Haugsten EM. (2011) Fibroblast growth factors and their receptors in cancer. Biochem J, 437 (2): 199-213. [PMID:21711248]

8. Yeh BK, Igarashi M, Eliseenkova AV, Plotnikov AN, Sher I, Ron D, Aaronson SA, Mohammadi M. (2003) Structural basis by which alternative splicing confers specificity in fibroblast growth factor receptors. Proc Natl Acad Sci USA, 100 (5): 2266-71. [PMID:12591959]

9. Zhao G, Li WY, Chen D, Henry JR, Li HY, Chen Z, Zia-Ebrahimi M, Bloem L, Zhai Y, Huss K et al.. (2011) A novel, selective inhibitor of fibroblast growth factor receptors that shows a potent broad spectrum of antitumor activity in several tumor xenograft models. Mol Cancer Ther, 10 (11): 2200-10. [PMID:21900693]

10. Zhou W, Hur W, McDermott U, Dutt A, Xian W, Ficarro SB, Zhang J, Sharma SV, Brugge J, Meyerson M et al.. (2010) A structure-guided approach to creating covalent FGFR inhibitors. Chem Biol, 17 (3): 285-95. [PMID:20338520]