FGFR-2 is a member of thefibroblast growth factor receptor family, where amino acid sequence is highly conserved between members and throughout evolution.[7] FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein consists of an extracellular region, composed of threeimmunoglobulin domains, a singlehydrophobic membrane-spanning segment and acytoplasmictyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencingmitogenesis anddifferentiation. This particular family member is a high-affinity receptor for acidic, basic and/orkeratinocyte growth factor, depending on theisoform.
FGFR2 has important roles in embryonic development and tissue repair, especially bone and blood vessels. Like the other members of thefibroblast growth factor receptor family, thesereceptors signal by binding to theirligand anddimerisation (pairing of receptors), which causes the tyrosine kinase domains to initiate a cascade of intracellular signals. On a molecular level these signals mediate cell division, growth and differentiation.
FGFR2 has two naturally occurring isoforms, FGFR2IIIb and FGFR2IIIc, created by splicing of the third immunoglobulin-like domain. FGFR2IIIb is predominantly found inectoderm derived tissues andendothelial organ lining, i.e. skin and internal organs.[8] FGFR2IIIc is found inmesenchyme, which includescraniofacial bone and for this reason the mutations of this gene and isoform are associated withcraniosynostosis.
Mutations (changes) are associated with numerous medical conditions that include abnormal bone development (e.g. craniosynostosis syndromes) and cancer.
Breast cancer, a mutation orsingle nucleotide polymorphism (SNP) inintron 2 of the FGFR2gene is associated with a higher breast cancer risk; however the risk is only mildly increased from about 10% lifetime breast cancer risk in the average woman in the industrialized world, to 12-14% risk in carriers of the SNP.[14]
AZD4547 is a tyrosine kinase inhibitor which targets FGFR1-3. It has demonstrated early evidence of efficacy ingastric cancer patients with high level FGFR2 amplification (Cancer Discovery 2016).FPA144 is amonoclonal antibody that binds to FGFR2b (a form of FGFR2) and preventing binding of certain FGFs. In 2014, a clinical trial began to treat gastric tumours that overexpress FGFR2b.[16]Another approach of FGFR2 targeting is use ofallosteric inhibitors.Alofanib is a novel first-in-class allosteric small-molecular inhibitor of FGFR2. It binds to the extracellular domain of FGFR2 and has an inhibitory effect on FGF2-inducedphosphorylation. Principal benefits of allosteric inhibitors are high selectivity and lowtoxicity [Tsimafeyeu et al. ESMO Asia 2016]. A phase Ib clinical study protocol has been selected for ECCO-AACR-EORTC-ESMO Workshop on Methods in Clinical Cancer Research, better known as the ‘Flims’ Workshop and clinical study of safety and preliminary efficacy of alofanib will be initiated at the beginning of 2017.
FGFR2 mutations are associated withcraniosynostosis syndromes, which are skull malformations caused by premature fusion of cranial sutures and other disease features according to the mutation itself. Analysis of chromosomal anomalies in patients led to the identification and confirmation of FGFR2 as a cleft lip and/or palate locus.[17] On a molecular level, mutations that affect FGFR2IIIc are associated with marked changes inosteoblast proliferation and differentiation.[18] Alteration in FGFR2 signalling is thought to underlie the craniosynostosis syndromes. To date, there are two mechanisms of altered FGFR2 signalling. The first is associated with constitutive activation of FGFR, where the FGFR2 receptor is always signalling, regardless of the amount of FGF ligand.[19] This mechanism is found in patients with Crouzon and Pfeiffer syndrome. The second, which is associated with Apert syndrome is a loss of specificity of the FGFR2 isoform, resulting in the receptor binding to FGFs that it does not normally bind.[20]
^Orr-Urtreger A, Bedford MT, Burakova T, Arman E, Zimmer Y, Yayon A, Givol D, Lonai P (Aug 1993). "Developmental localization of the splicing alternatives of fibroblast growth factor receptor-2 (FGFR2)".Developmental Biology.158 (2):475–86.doi:10.1006/dbio.1993.1205.PMID8393815.
Park WJ, Meyers GA, Li X, Theda C, Day D, Orlow SJ, Jones MC, Jabs EW (Jul 1995). "Novel FGFR2 mutations in Crouzon and Jackson–Weiss syndromes show allelic heterogeneity and phenotypic variability".Human Molecular Genetics.4 (7):1229–33.doi:10.1093/hmg/4.7.1229.PMID8528214.
Marie PJ, Debiais F, Haÿ E (2003). "Regulation of human cranial osteoblast phenotype by FGF-2, FGFR-2 and BMP-2 signaling".Histology and Histopathology.17 (3):877–85.doi:10.14670/HH-17.877.PMID12168799.
