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

Abstract

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.