biostudies-literatureJones RTNational Cancer Institute (NCI)Anschutz Family FoundationNational Cancer InstituteErasmus Medisch Centrum (EMC)NCI NIH HHSNational Institute of General Medical SciencesFinnish Cancer Institute (Suomen syöpälaitos)NIGMS NIH HHSNational Institute of General Medical Sciences (NIGMS)Erasmus Medisch CentrumFinnish Cancer Institute1699-1718https://www.ebi.ac.uk/biostudies/studies/S-EPMC11094426biostudies-literatureUnknown84(10)There is an unmet need to improve the efficacy of platinum-based cancer chemotherapy, which is used in primary and metastatic settings in many cancer types. In bladder cancer, platinum-based chemotherapy leads to better outcomes in a subset of patients when used in the neoadjuvant setting or in combination with immunotherapy for advanced disease. Despite such promising results, extending the benefits of platinum drugs to a greater number of patients is highly desirable. Using the multiomic assessment of cisplatin-responsive and -resistant human bladder cancer cell lines and whole-genome CRISPR screens, we identified puromycin-sensitive aminopeptidase (NPEPPS) as a driver of cisplatin resistance. NPEPPS depletion sensitized resistant bladder cancer cells to cisplatin in vitro and in vivo. CCancer researchNPEPPS Is a Druggable Driver of Platinum Resistance.PMC11094426R01 CA180175P30 CA046934CA268055107088CA046934T32 GM008497111296CA180175R01 CA268055GM008497T32 GM007635GM007635Vekony HJones RTMahmoudi TXander NRomal SGoodspeed AFeldman LEZuiverloon TCMLayer RClambey ETCostello JCJoshi MAraki SPScholtes MJean AKan TWTheodorescu DMohapatra STilton CBParker SJAkbarzadeh MDeiter CJavaid MOrman MVLaajala TDfalseNPEPPS Is a Druggable Driver of Platinum Resistance.There is an unmet need to improve the efficacy of platinum-based cancer chemotherapy, which is used in primary and metastatic settings in many cancer types. In bladder cancer, platinum-based chemotherapy leads to better outcomes in a subset of patients when used in the neoadjuvant setting or in combination with immunotherapy for advanced disease. Despite such promising results, extending the benefits of platinum drugs to a greater number of patients is highly desirable. Using the multiomic assessment of cisplatin-responsive and -resistant human bladder cancer cell lines and whole-genome CRISPR screens, we identified puromycin-sensitive aminopeptidase (NPEPPS) as a driver of cisplatin resistance. NPEPPS depletion sensitized resistant bladder cancer cells to cisplatin in vitro and in vivo. C2024-01-01T00:00:00Z2024 May2026-06-01T05:25:57.363Z2025-08-27T03:08:53.289ZS-EPMC110944263853599410.1158/0008-5472.CAN-23-1976