Spectrum of genomic alterations in FGFR3: current appraisal of the potential role of FGFR3 in advanced urothelial carcinoma

Abstract

Molecular analysis has identified subsets of urothelial carcinoma (UC) expressing distinct genetic signatures. Genomic alterations in the oncogenic fibroblast growth factor receptor 3 (FGFR3) pathway are among the most well described in UC and have led to extensive and ongoing investigation of FGFR3-targeted therapies in this disease, although no new drugs have yet been approved. Given the unmet need for effective treatments in advanced and metastatic UC, a better understanding of the known molecular alterations of FGFR3 and of the previous and ongoing clinical investigations of this promising target in UC deserves attention. The objective of the present review is to describe the landscape of alterations and biology of FGFR3 in UC, comprehensively summarize the current state of UC clinical trials of FGFR3 inhibitors, and discuss future therapeutic applications. Using the Pubmed and Clinicaltrials.gov databases, articles describing the spectrum and biological activity of FGFR3 genomic alterations and trials of FGFR3 inhibitors in UC were identified. Search terms included ‘FGFR3 genomic alterations’ and ‘urothelial cancer’ or ‘bladder cancer’. Genomic alterations, including translocations and activating mutations, are increasingly described in advanced and metastatic UC. The majority of clinical trials have been performed in unselected populations; however, recent studies have reported encouraging preliminary data. We argue that routine use of molecular genomic tumour analysis in UC may inform selection of patients for appropriate trials and we further investigate the potential of FGFR3 as a meaningful clinical target for this difficult disease.