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

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Bladder cancer (BC) is a common malignancy with frequent FGFR3 alterations.
• Current FGFR inhibitors like erdafitinib show limited durable responses, necessitating novel therapeutic strategies.
• FGFR3 alterations are a key driver in a subset of BC cases.

Purpose of the Study:

• To investigate the synergistic potential of combining FGFR inhibitors with histone deacetylase (HDAC) inhibitors for treating BC.
• To explore the mechanistic basis of this synergy in preclinical models of BC.
• To identify new therapeutic avenues for patients with FGFR3-driven metastatic BC.

Main Methods:

• In vitro and in vivo preclinical models of bladder cancer.
• Combination treatment with erdafitinib (FGFR inhibitor) and quisinostat (HDAC inhibitor).
• Assessment of FGFR3 expression, translation, HDGF levels, and cell viability.

Main Results:

• Synergy was confirmed between FGFR and HDAC inhibitors in vitro and in vivo.
• Quisinostat suppressed FGFR3 expression by inhibiting its translation.
• Quisinostat sensitized BC cells to erdafitinib by downregulating HDGF, including in cells with FGFR3 S249C mutation.

Conclusions:

• The combination of FGFR and HDAC inhibitors represents a novel and effective therapeutic strategy for FGFR3-driven BC.
• Mechanistic insights reveal quisinostat's role in downregulating FGFR3 and sensitizing cells to erdafitinib.
• These findings support the translation of this combination therapy into early-phase clinical trials for bladder cancer.