Fibroblast growth factor receptor (FGFR) family aberrations are common in urothelial cancer. The FGFR tyrosine kinase inhibitor erdafitinib has been approved for locally advanced or metastatic urothelial cancer with FGFR2/3 alterations. Despite the initial efficacy of erdafitinib, resistance cannot be avoided. The molecular mechanisms underlying erdafitinib resistance have not been well investigated. Here, genome-wide CRISPR screen is performed and coatomer protein complex subunit α (COPA) is identified as a key target to enhance erdafitinib sensitivity. Functionally, the deficiency of COPA reduces the proliferation of FGFR-altered bladder cancer cells upon erdafitinib treatment. Mechanistically, COPA knockout increases the degradation of leucine-rich pentatricopeptide repeat containing (LRPPRC) protein, leading to reduced inhibitor of DNA binding 3 (ID3) mRNA stability in an m6A-dependent manner. Collectively, these findings reveal a novel mechanism of erdafitinib resistance, providing a potential therapeutic target for FGFR-altered bladder cancer.