Cisplatin-based chemotherapy is used across many common tumor types, but resistance reduces the likelihood of long-term survival. We previously found the puromycin-sensitive aminopeptidase, NPEPPS, as a druggable driver of cisplatin resistance in vitro and in vivo and in patient-derived organoids. Here, we present a general mechanism where NPEPPS interacts with the volume-regulated anion channels (VRACs) to control cisplatin import into cells and thus regulate cisplatin response across a range of cancer types. We also find the NPEPPS/VRAC gene expression ratio is a predictive measure of cisplatin response in multiple cancer cohorts, showing the broad applicability of this mechanism. Our work describes a specific mechanism of cisplatin resistance, which, given the characteristics of NPEPPS as a drug target, has the potential to improve cancer patient outcomes. In addition, we describe an intracellular mechanism regulating VRAC activity, which is critical for volume regulation in normal cells – a finding with functional implications beyond cancer.

中文翻译：

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调节容量调节阴离子通道会改变对铂类化疗的敏感性


基于顺铂的化疗用于许多常见的肿瘤类型，但耐药性降低了长期生存的可能性。我们之前发现嘌呤霉素敏感的氨肽酶 NPEPPS 是体外和体内以及患者来源的类器官中顺铂耐药的可成药驱动因素。在这里，我们提出了一种一般机制，其中 NPEPPS 与体积调节阴离子通道 （VRAC） 相互作用以控制顺铂输入细胞，从而调节一系列癌症类型的顺铂反应。我们还发现 NPEPPS/VRAC 基因表达比值是多个癌症队列中顺铂反应的预测指标，显示了这种机制的广泛适用性。我们的工作描述了顺铂耐药的特定机制，鉴于 NPEPPS 作为药物靶点的特性，该机制有可能改善癌症患者的预后。此外，我们描述了一种调节 VRAC 活性的细胞内机制，这对正常细胞的体积调节至关重要——这一发现在癌症之外具有功能意义。