In this review, we revisit the pivotal role of fibroblast growth factor receptor 3 (FGFR3) in bladder cancer (BLCA), underscoring its prevalence in both non-muscle-invasive and muscle-invasive forms of the disease. FGFR3 mutations in up to half of BLCAs play a well-established role in tumorigenesis, shaping distinct tumor initiation patterns and impacting the tumor microenvironment (TME). Emphasizing the importance of considering epithelial-mesenchymal transition profile and TME status, we revisit their relevance in predicting responses to immune checkpoint inhibitors in FGFR3-mutated BLCAs. This writing highlights the initially promising yet transient efficacy of the FGFR inhibitor Erdafitinib on FGFR3-mutated BLCA, stressing the pressing need to unravel resistance mechanisms and identify co-targets for future combinatorial studies. A thorough analysis of recent preclinical and clinical evidence reveals resistance mechanisms, including secondary mutations, epigenetic alterations in pathway effectors, phenotypic heterogeneity, and population-specific variations within FGFR3 mutational status. Lastly, we discuss the potential of combinatorial treatments and concepts like synthetic lethality for discovering more effective targeted therapies against FGFR3-mutated BLCA.
Cancer communications (London, England). 2024 Aug 19 [Epub ahead of print]
Maxim Noeraparast, Katarina Krajina, Renate Pichler, Dora Niedersüß-Beke, Shahrokh F Shariat, Viktor Grünwald, Sascha Ahyai, Martin Pichler
Translational Oncology, II. Med Clinics Hematology and Oncology, Augsburg, Germany., Department of Urology, Medical University of Innsbruck, Innsbruck, Austria., Department of Hematology and Oncology, Clinics Ottakring, Vienna, Austria., Department of Urology, Medical University of Vienna, Vienna, Austria., Interdisciplinary Genitourinary Oncology, Clinic for Urology, Clinic for Medical Oncology, University Hospital Essen, Hufelandstraße 55, Essen, Germany., Department of Urology, Medical University of Graz, Graz, Austria.