There is an unmet need to improve efficacy of platinum-based cancer chemotherapy. Using multi-omic assessment of cisplatin-responsive and -resistant human bladder cancer cell lines and whole-genome CRISPR screens, we identified Puromycin-Sensitive Aminopeptidase, NPEPPS, as a novel driver of cisplatin resistance. NPEPPS depletion sensitizes resistant bladder cancer cells to cisplatin in vitro and in vivo. Conversely, overexpression of NPEPPS in sensitive cells increased cisplatin resistance. We show that NPEPPS affects treatment response by regulating intracellular cisplatin concentrations. Patient-derived organoids (PDOs) generated from bladder cancer samples before and after cisplatin-based treatment, and from patients who did not receive cisplatin, were evaluated for sensitivity to cisplatin and they were found to be concordant with clinical response. In PDOs, shRNA depletion or pharmacologic inhibition of NPEPPS led to increased cisplatin sensitivity, while NPEPPS overexpression had the opposite effect. Our data present NPEPPS as a novel and druggable driver of cisplatin resistance by regulating intracellular cisplatin concentrations, along with providing the preclinical data to support clinical trials combining NPEPPS inhibition with cisplatin.

中文翻译：

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NPEPPS 是一种新型的、可药物化的铂耐药驱动因素

提高铂类癌症化疗疗效的需求尚未得到满足。通过对顺铂敏感和耐药的人膀胱癌细胞系进行多组学评估和全基因组 CRISPR 筛选，我们发现嘌呤霉素敏感氨肽酶 (NPEPPS) 是顺铂耐药的新驱动因素。NPEPPS 耗竭使耐药膀胱癌细胞在体外和体内对顺铂敏感。相反，敏感细胞中 NPEPPS 的过度表达会增加顺铂耐药性。我们发现 NPEPPS 通过调节细胞内顺铂浓度来影响治疗反应。对顺铂治疗前后的膀胱癌样本以及未接受顺铂的患者产生的患者来源的类器官（PDO）进行了顺铂敏感性评估，发现它们与临床反应一致。在 PDO 中，shRNA 耗竭或 NPEPPS 的药理学抑制导致顺铂敏感性增加，而 NPEPPS 过度表达则具有相反的效果。我们的数据表明，NPEPPS 通过调节细胞内顺铂浓度，成为顺铂耐药的新型可药物驱动因素，并提供临床前数据来支持 NPEPPS 抑制与顺铂相结合的临床试验。