Pyrvinium is a quinoline-derived cyanine dye and an approved anti-helminthic drug reported to inhibit WNT signaling and have anti-proliferative effects in various cancer cell lines. To further understand the mechanism by which pyrvinium is cytotoxic, we conducted a pooled genome-wide CRISPR loss-of-function screen in the human HAP1 cell model. The top drug–gene sensitizer interactions implicated the malate–aspartate and glycerol-3-phosphate shuttles as mediators of cytotoxicity to mitochondrial complex I inhibition including pyrvinium. By contrast, perturbation of the poorly characterized gene C1orf115/RDD1 resulted in strong resistance to the cytotoxic effects of pyrvinium through dysregulation of the major drug efflux pump ABCB1/MDR1. Interestingly, C1orf115/RDD1 was found to physically associate with ABCB1/MDR1 through proximity-labeling experiments and perturbation of C1orf115 led to mis-localization of ABCB1/MDR1. Our results are consistent with a model whereby C1orf115 modulates drug efflux through regulation of the major drug exporter ABCB1/MDR1.

Pyrvinium 是一种喹啉衍生的花青染料和一种经批准的抗蠕虫药物，据报道可抑制 WNT 信号传导，并在各种癌细胞系中具有抗增殖作用。为了进一步了解吡维铵具有细胞毒性的机制，我们在人类 HAP1 细胞模型中进行了全基因组 CRISPR 功能丧失筛选。最主要的药物-基因致敏剂相互作用表明苹果酸-天冬氨酸和甘油-3-磷酸穿梭作为线粒体复合物 I 抑制（包括吡维铵）的细胞毒性介质。相比之下，对特征较差的基因C1orf115/RDD1的扰动通过主要药物外排泵 ABCB1/MDR1 的失调，导致对吡维铵的细胞毒性作用产生强烈抵抗。有趣的是，通过邻近标记实验发现 C1orf115/RDD1 与 ABCB1/MDR1 物理关联，并且C1orf115的扰动导致 ABCB1/MDR1 的错误定位。我们的结果与 C1orf115 通过调节主要药物出口商 ABCB1/MDR1 调节药物流出的模型一致。