Abstract
BACKGROUND: Advanced urothelial carcinoma (UC) is an aggressive disease whose mutagenic processes are yet to be elucidated. Targeted therapies are urgently needed, but the road from bench to bedside is slowly progressing. In this review, we discuss urothelial carcinoma etiology, along with the most recent advances in UC candidate targeted therapies. METHODOLOGY: A comprehensive database search was performed. We aimed to review the most recent updates on UC genomics and targeted therapies. Pre-clinical as well as clinical studies were included. RESULTS: Our review highlights the advances in understanding the molecular basis of urothelial tumorigenesis, including smoking, chemical parasitic carcinogens, inheritance, and APOBEC3 editing enzymes. We discussed how these factors contributed to the current mutational landscape of UC. Therapeutic options for UC are still very limited. However, several promising therapeutic approaches are in development to leverage our knowledge of molecular targets, such as targeting fibroblast growth factor receptors (FGFR), DNA damage repair pathways, and HER2. CONCLUSIONS: Blindly testing targeted therapies based on other cancer data is not sufficient. UC-specific biomarkers are needed to precisely use the appropriate drug for the appropriate population. More efforts to understand UC biology and evolution are urgently needed.