Tackling FGFR3-driven bladder cancer with a promising synergistic FGFR/HDAC targeted therapy

Abstract

Abstract Bladder cancer (BC) is one of the most prevalent malignancies worldwide and FGFR3 alterations are particularly common in BC. Despite approval of erdafitinib, durable responses for FGFR inhibitors are still uncommon and most patients relapse to metastatic disease. Given the necessity to discover more efficient therapies for BC, herein, we sought to explore promising synergistic combinations for BC with FGFR3 fusions. Our studies confirmed the synergy between FGFR and HDAC inhibitors in vitro and demonstrated its benefits in vivo. Mechanistic studies revealed that quisinostat can downregulate FGFR3 expression by suppressing FGFR3 translation. Additionally, quisinostat can also sensitize BC cells to erdafitinib by downregulating HDGF. Furthermore, the synergy was also confirmed in BC cells with FGFR3 S249C. This study discovers a new avenue for treatment of FGFR3-driven BC and uncovers new mechanistic insights. These preclinical studies pave the way for a direct translation of this combination to early phase clinical trials.