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. Conversely, overexpression of NPEPPS in sensitive cells increased cisplatin resistance. NPEPPS affected treatment response by regulating intracellular cisplatin concentrations. Patient-derived organoids (PDO) 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, which was concordant with clinical response. In the PDOs, depletion or pharmacologic inhibition of NPEPPS increased cisplatin sensitivity, whereas NPEPPS overexpression conferred resistance. Our data present NPEPPS as a druggable driver of cisplatin resistance by regulating intracellular cisplatin concentrations. Significance: Targeting NPEPPS, which induces cisplatin resistance by controlling intracellular drug concentrations, is a potential strategy to improve patient responses to platinum-based therapies and lower treatment-associated toxicities.

中文翻译：

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NPEPPS 是铂耐药性的药物驱动因素

提高铂类癌症化疗的疗效的需求尚未得到满足，该化疗用于许多癌症类型的原发性和转移性环境。在膀胱癌中，铂类化疗在新辅助治疗或与晚期疾病的免疫疗法联合使用时，可以为部分患者带来更好的结果。尽管取得了如此有希望的结果，但将铂类药物的益处扩展到更多患者仍然是非常理想的。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。 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) 进行了评估，以评估其对顺铂的敏感性，这与临床反应一致。在 PDO 中，NPEPPS 的耗竭或药物抑制会增加顺铂敏感性，而 NPEPPS 过度表达会产生耐药性。我们的数据表明 NPEPPS 通过调节细胞内顺铂浓度作为顺铂耐药的药物驱动因素。意义：针对 NPEPPS（通过控制细胞内药物浓度诱导顺铂耐药）是改善患者对铂类治疗的反应并降低治疗相关毒性的潜在策略。