Targeting COPA to Enhance Erdafitinib Sensitivity in FGFR-Altered Bladder Cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Fibroblast growth factor receptor (FGFR) aberrations are prevalent in urothelial cancer.
• Erdafitinib, an FGFR tyrosine kinase inhibitor, is approved for advanced urothelial cancer with FGFR2/3 alterations.
• Mechanisms of erdafitinib resistance remain incompletely understood.

Purpose of the Study:

• To investigate the molecular mechanisms of erdafitinib resistance in urothelial cancer.
• To identify novel therapeutic targets for enhancing erdafitinib sensitivity.

Main Methods:

• Genome-wide CRISPR screening was employed to identify genetic modifiers of erdafitinib sensitivity.
• Functional assays were conducted to assess the role of identified targets in cancer cell proliferation.
• Molecular mechanisms involving protein degradation and mRNA stability were investigated.

Main Results:

• Coatomer protein complex subunit α (COPA) was identified as a key target that enhances erdafitinib sensitivity.
• COPA deficiency reduced the proliferation of FGFR-altered bladder cancer cells treated with erdafitinib.
• COPA knockout led to increased degradation of LRPPRC, reducing ID3 mRNA stability in an m6A-dependent manner.

Conclusions:

• This study reveals a novel mechanism of erdafitinib resistance mediated by COPA.
• Targeting COPA presents a potential therapeutic strategy for overcoming erdafitinib resistance in FGFR-altered bladder cancer.