Fibroblast growth factor receptor-3 in urothelial tumorigenesis

Fibroblast growth factor receptor-3 (FGFR3) is a receptor tyrosine kinase implicated in the tumorigenesis of multiple malignancies, including bladder and other urothelial cancers, multiple myeloma, and cervical cancer. In urothelial carcinoma (UC), constitutive receptor activation occurs most commonly through substitution of a wild-type residue with cysteine in the extracellular domain of FGFR3, thereby resulting in dimerization (through disulfide bridge formation) and subsequent stimulation of tyrosine kinase activity. Activating mutations of FGFR3 have been observed in up to 70% of non-muscle-invasive bladder tumors, while overexpression of a wild-type receptor, found in approximately 40% of tumors, has been correlated with more invasive disease. The identification of FGFR3 mutations in UC has sparked substantial interest in the therapeutic exploitation of these aberrations, and in vitro studies have provided evidence that such alterations may represent driver oncogenic lesions. In this review, we discuss the biologic and prognostic impact of FGFR3 mutations in UC as well as FGFR3 as a potential target for novel therapeutics.