Abstract
Simple SummaryAll cells within tissues and organ systems must communicate with each other to ensure they function in a coordinated manner. One form of communication is signalling mediated by small proteins (for example fibroblast growth factors; FGFs) that are secreted by one cell and bind to specialised receptors (for example FGF receptors) on nearby cells. These receptors propagate the signal to the nucleus of the receiving cell, which in turn dictates to the cell how it should react. FGFR signalling is versatile, tightly controlled and important for normal body homeostasis, facilitating growth, healing and replacing old cells. However, cancer cells can take command of this pathway and use it to their advantage. This review will first explain the biology of FGFR signalling and then describe how it can be corrupted, the implications in cancer, and how it can be targeted to improve cancer therapy.The pleiotropic effects of fibroblast growth factors (FGFs), the widespread expression of all seven signalling FGF receptors (FGFRs) throughout the body, and the dramatic phenotypes shown by many FGF/R knockout mice, highlight the diversity, complexity and functional importance of FGFR signalling. The FGF/R axis is critical during normal tissue development, homeostasis and repair. Therefore, it is not surprising that substantial evidence also pinpoints the involvement of aberrant FGFR signalling in disease, including tumourigenesis. FGFR aberrations in cancer include mutations, gene fusions, and amplifications as well as corrupted autocrine/paracrine loops. Indeed, many clinical trials on cancer are focusing on targeting the FGF/FGFR axis, using selective FGFR inhibitors, nonselective FGFR tyrosine kinase inhibitors, ligand traps, and monoclonal antibodies and some have already been approved for the treatment of cancer patients. The heterogeneous tumour microenvironment and complexity of FGFR signalling may be some of the factors responsible for the resistance or poor response to therapy with FGFR axis-directed therapeutic agents. In the present review we will focus on the structure and function of FGF(R)s, their common irregularities in cancer and the therapeutic value of targeting their function in cancer.
Highlights
FGF receptors (FGFRs) fusions are relatively rare in human cancers it might be of interest to identify how patients with FGFR fusions respond to therapy targeting the tyrosine kinase (TK) domain of FGFR
Experimental data and clinical trials focusing on targeting the FGFR axis have demonstrated positive outcomes
FGFR acts via a paracrine or autocrine mechanism in a specific tumour) is important for tailoring combinations of targeted therapies aiming at the FGFR axis
Summary
Acknowledging that many other tyrosine kinase receptors merit therapeutic targeting, this review will focus and discuss further the importance and different ways of targeting the FGF/FGFR axis. The interaction between the acidic box and the heparan sulphate-binding site inhibits activation of the receptor when FGF is absent [8,14,15,16]. Aside from the four main FGFR family members (FGFR1–4), there is an additional receptor, fibroblast growth factor receptor like 1 (FGFRL1 or FGFR5), that can bind to FGFs and heparin, but lacks the tyrosine kinase domain and cannot signal via transphosphorylation [19]. FGFR1L is believed to negatively regulate FGFR signalling by acting as a decoy receptor that neutralises FGFs by binding to them without activating any downstream signalling cascade [20]. Binding of FGF8 to FGFRL1 plays an important role in developing kidneys by driving the formation of nephrons [22]
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