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  • br Future perspectives A plethora of

    2021-09-18


    Future perspectives A plethora of reports from in vivo and in vitro human and animal studies have demonstrated the potential role of FGFR signalling in human carcinogenesis, whether it be in an oncogenic or tumour suppressive capacity. It is still not well understood how FGFRs can act as tumour suppressors, and this mechanism must be further elucidated before we start to target FGFR as a therapeutic target in human diseases. Indeed, up-regulating these tumour suppressor isoforms of FGFR2 may provide an alternative strategy for pharmaceutical developments. It is also crucial that the tumours that are ‘driven’ by activation of FGF signalling are distinguished from those that merely have FGF signalling as a ‘passenger’. In summary, it can be considered that some tumours rely on deregulated FGF signalling on their development and progression, and as such FGF signalling CGP 54626 hydrochloride provides an attractive target for treatment. This is promising since multiple agents are now in the pipelines for preclinical and clinical evaluation.
    Acknowledgements IA is funded by a MRC clinical research training fellowship. HYL's research programme is funded by Cancer Research U.K.
    Fibroblast growth factor (FGF) receptors (FGFR1–4) comprise a family of transmembrane (TM) tyrosine kinases that bind 18 fgf ligands with high affinity in the presence of heparan sulfate . They are composed of extracellular (EC) portions built of three Ig-like domains (D1, D2, and D3), single TM domains, and intracellular kinase domains , . These receptors play key roles in the regulation of cell differentiation, migration, proliferation, and apoptosis . They are required for embryonic development, lung morphogenesis, osteogenesis, and limb bud development , . The FGFRs belong to the large family of receptor tyrosine kinases (RTKs) . Like all RTKs, they are activated upon lateral dimerization in the cellular membrane, which brings the two kinases in close proximity , , . In the dimer, the two kinases activate each other by cross-phosphorylating the tyrosines in the kinase activation loop. For many years, dimerization was believed to occur only in response to ligand binding . However, recent work has demonstrated that dimerization can also occur in the absence of ligand because the FGFRs have intrinsic sequence-specific propensities for lateral interactions , . The FGFRs are known to harbor many pathogenic mutations , . As germ-line mutations, they cause developmental abnormalities of the skeletal system , , , , , , . As somatic mutations, they have been linked to various cancers , . Some of these mutations are believed to cause pathologies by stabilizing the active FGFR dimers . In particular, mutations that introduce or remove cysteine residues are believed to belong to this category . Indeed, the unpaired cysteines can form disulfide bonds that bridge two receptors, leading to constitutive dimerization. Here, we study the effect of three cysteine mutations in FGFR1, FGFR2, and FGFR3 on the stability of full-length FGF dimers. The first mutation that we investigate is the C178S mutation in the first Ig-like domain (D1) of FGFR1, which is associated with Kallman syndrome . The phenotype includes severe ear anomalies (hypoplasia of the external ear), failure to start puberty, infertility, and complete lack of sense of smell. It occurs in 1 in 10,000 men and 1 in 50,000 women . The second mutation that we study is the C342R mutation in the third Ig-like domain (D3) of FGFR2. This mutation is found in individuals with Crouzon syndrome, Jackson–Weiss syndrome, Pfeiffer syndrome, and Antley–Bixler-like syndrome , , , , , , , , , , , . Crouzon syndrome is characterized by the premature fusion of skull sutures (craniosynostosis) and has an incident rate of 1 in 25000 individuals . The Jackson–Weiss syndrome phenotype is characterized by craniosynostosis and foot abnormalities. The features of Pfeiffer syndrome are short fingers and soft-tissue syndactyly, while the Antley–Bixler-like syndrome phenotype includes craniofacial and limb abnormalities , , , . The third mutation that we investigate is C228R, which is located in the second Ig-like domain (D2) of FGFR3 and linked to colorectal cancer carcinoma , the most common type of intestinal cancer with 140,000 new cases each year in the United States alone.