An FGFR3/MYC positive feedback loop provides new opportunities for targeted therapies in bladder cancers

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Fibroblast Growth Factor Receptor 3 (FGFR3) alterations are common in bladder carcinoma.
• These alterations lead to aberrant FGFR3 signaling, creating an oncogenic dependence.

Purpose of the Study:

• To investigate the molecular mechanisms driving FGFR3-driven bladder cancer.
• To identify potential therapeutic targets within the FGFR3 signaling pathway.

Main Methods:

• Investigated a positive feedback loop involving FGFR3, p38, AKT, and MYC.
• Utilized FGFR3, p38, AKT, and BET bromodomain inhibitors (JQ1) in bladder cancer cell lines.
• Assessed cell viability in vitro and tumor growth in vivo.
• Correlated FGFR3 and MYC levels in human bladder tumors and a patient-derived xenograft (PDX) model.

Main Results:

• Discovered a positive feedback loop where altered FGFR3 upregulates MYC, which in turn upregulates FGFR3 expression.
• Inhibition of this FGFR3/MYC loop decreased cell viability and tumor growth.
• Found a positive correlation between FGFR3 and MYC levels in tumors with FGFR3 mutations.
• Observed decreased FGFR3 and MYC levels after anti-FGFR treatment in a relevant PDX model.

Conclusions:

• The identified FGFR3/MYC feedback loop is crucial for bladder tumor growth.
• Targeting components of this loop, including FGFR3, p38, AKT, or MYC, presents a promising therapeutic strategy.
• These findings offer new avenues for treating bladder tumors with aberrant FGFR3 activation.