Background Drug resistance is a major obstacle in cancer therapy. To elucidate the genetic factors that regulate sensitivity to anti-cancer drugs, we performed CRISPR-Cas9 knockout screens for resistance to a spectrum of drugs. Results In addition to known drug targets and resistance mechanisms, this study revealed novel insights into drug mechanisms of action, including cellular transporters, drug target effectors, and genes involved in target-relevant pathways. Importantly, we identified ten multi-drug resistance genes, including an uncharacterized gene C1orf115 , which we named Required for Drug-induced Death 1 ( RDD1 ). Loss of RDD1 resulted in resistance to five anti-cancer drugs. Finally, targeting RDD1 leads to chemotherapy resistance in mice and low RDD1 expression is associated with poor prognosis in multiple cancers. Conclusions Together, we provide a functional landscape of resistance mechanisms to a broad range of chemotherapeutic drugs and highlight RDD1 as a new factor controlling multi-drug resistance. This information can guide personalized therapies or instruct rational drug combinations to minimize acquisition of resistance.

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癌症多药耐药基因的系统功能鉴定

背景 耐药性是癌症治疗的主要障碍。为了阐明调节抗癌药物敏感性的遗传因素，我们对一系列药物进行了 CRISPR-Cas9 基因敲除筛选。结果 除了已知的药物靶点和耐药机制外，这项研究还揭示了对药物作用机制的新见解，包括细胞转运蛋白、药物靶标效应物和参与靶标相关通路的基因。重要的是，我们确定了十个多药耐药基因，包括一个未表征的基因 C1orf115 ，我们将其命名为药物诱导死亡 1 ( RDD1 ) 所需。RDD1 的缺失导致对五种抗癌药物的耐药性。最后，靶向 RDD1 会导致小鼠的化疗耐药，而 RDD1 的低表达与多种癌症的不良预后相关。结论一起，我们为广泛的化疗药物提供了耐药机制的功能景观，并强调了 RDD1 作为控制多药耐药性的新因素。该信息可以指导个性化治疗或指导合理的药物组合，以最大限度地减少耐药性的产生。