Biological Significance and Targeting of the FGFR Axis in Cancer

SIMPLE SUMMARY: All 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. ABSTRACT: 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.