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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\u2010wide CRISPR screen is performed and coatomer protein complex subunit \u03b1 (COPA) is identified as a key target to enhance erdafitinib sensitivity. Functionally, the deficiency of COPA reduces the proliferation of FGFR\u2010altered bladder cancer cells upon erdafitinib treatment. Mechanistically, COPA knockout increases the degradation of leucine\u2010rich pentatricopeptide repeat containing (LRPPRC) protein, leading to reduced inhibitor of DNA binding 3 (ID3) mRNA stability in an m6A\u2010dependent manner. Collectively, these findings reveal a novel mechanism of erdafitinib resistance, providing a potential therapeutic target for FGFR\u2010altered bladder cancer.<\/jats:p>","DOI":"10.1002\/advs.202413209","type":"journal-article","created":{"date-parts":[[2025,3,23]],"date-time":"2025-03-23T02:35:43Z","timestamp":1742697343000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Targeting COPA to Enhance Erdafitinib Sensitivity in FGFR\u2010Altered Bladder Cancer"],"prefix":"10.1002","volume":"12","author":[{"given":"Huayuan","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Urology Union Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan 430022 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xincheng","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Urology Union Hospital Tongji Medical College Huazhong University 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