Targeting COPA to enhance erdafitinib sensitivity in FGFR-altered bladder cancer

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 mechanism of erdafitinib resistance has not been well investigated. Here, we performed genome-wide CRISPR screen and identified coatomer protein complex subunit a (COPA) as a key target to enhance erdafitinib sensitivity. Functionally, the deficiency of COPA reduced the proliferation of FGFR-altered bladder cancer cells upon erdafitinib treatment. Mechanistically, COPA knockout increased LRPPRC protein degradation, leading to reduced 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. Overall design: To determine the target genes and downstream signaling pathways of COPA in bladder cancer cells, transcriptome analysis was performed in sg-NC and COPA-KO cells with DMSO or erdafitinib treatment.