A Decade of FGF Receptor Research in Bladder Cancer: Past, Present, and Future Challenges

Abstract

Fibroblast growth factors (FGFs) orchestrate a variety of cellular functions by binding to their transmembrane tyrosine-kinase receptors (FGFRs) and activating downstream signalling pathways, including RAS/MAPK, PLCγ1, PI3K, and STATs. In the last ten years, it has become clear that FGF signalling is altered in a high proportion of bladder tumours. Activating mutations and/or overexpression of FGFR3 are common in urothelial tumours with low malignant potential and low-stage and -grade urothelial carcinomas (UCs) and are associated with a lower risk of progression and better survival in some subgroups. FGFR1 is not mutated in UC, but overexpression is frequent in all grades and stages and recent data indicate a role in urothelial epithelial-mesenchymal transition. In vitro and in vivo studies have shown that FGFR inhibition has cytotoxic and/or cytostatic effects in FGFR-dependent bladder cancer cells and FGFR-targeted agents are currently being investigated in clinical studies for the treatment of UC. Urine-based tests detecting common FGFR3 mutations are also under development for surveillance of low-grade and -stage tumours and for general population screening. Overall, FGFRs hold promise as therapeutic targets, diagnostic and prognostic markers, and screening tools for early detection and clinical management of UC.

Figure 1

Schematic representation of human FGFR3 protein and corresponding FGFR3 coding exons. Exon numbering based on Tomlinson et al. [38]. Type and total number of reported mutations are based on data pooled from 11 studies [–, , , –42], including a total of 1898 bladder tumours. SP: signal peptide; IgI–III: immunoglobulin-like domain; AB: acid box; TM: transmembrane domain; TK; tyrosine-kinase domain.

Figure 2

Mechanisms of physiological (a)-(b) and pathological (c)–(f) activation of FGFR3. (a) Monomeric inactive receptor; (b) Ligand-dependent dimerization and activation; (c) Ligand-independent dimerization and activation induced by mutation of the extracellular portion; (d) Ligand-independent activation due to mutations of the tyrosine-kinase domain; (e) Upregulation of signalling due to receptor overexpression; (f) Alteration of splicing favouring isoforms with broader ligand specificity.

Figure 3

Potential applications of FGFRs in the early detection and clinical management of bladder tumours.