Solute carriers (SLCs) are the largest family of transmembrane transporters in humans and are major determinants of cellular metabolism. Several SLCs have been shown to be required for the uptake of chemical compounds into cellular systems, but systematic surveys of transporter–drug relationships in human cells are currently lacking. We performed a series of genetic screens in a haploid human cell line against 60 cytotoxic compounds representative of the chemical space populated by approved drugs. By using an SLC-focused CRISPR–Cas9 library, we identified transporters whose absence induced resistance to the drugs tested. This included dependencies involving the transporters SLC11A2/SLC16A1 for artemisinin derivatives and SLC35A2/SLC38A5 for cisplatin. The functional dependence on SLCs observed for a significant proportion of the screened compounds suggests a widespread role for SLCs in the uptake and cellular activity of cytotoxic drugs and provides an experimentally validated set of SLC–drug associations for a number of clinically relevant compounds.

溶质载体 (SLC) 是人类最大的跨膜转运蛋白家族，是细胞代谢的主要决定因素。已经证明，将化合物吸收到细胞系统中需要几种 SLC，但目前缺乏对人体细胞中转运蛋白-药物关系的系统调查。我们在单倍体人类细胞系中针对 60 种细胞毒性化合物进行了一系列基因筛选，这些化合物代表了已批准药物所占据的化学空间。通过使用以 SLC 为中心的 CRISPR-Cas9 文库，我们确定了转运蛋白的缺失会导致对测试药物产生耐药性。这包括涉及青蒿素衍生物转运蛋白 SLC11A2/SLC16A1 和顺铂转运蛋白 SLC35A2/SLC38A5 的依赖性。