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.
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We thank all members of the Superti-Furga laboratory for discussions and feedback. We are also grateful to the Biomedical Sequencing facility for advice on Illumina sequencing and to the Flow Cytometry Core Facility of the Vienna Medical University for help with FACS sorting. We also thank B. Vilagos for graphical input and advice and S. Sdelci for scientific discussions and insights. We acknowledge support by the Austrian Academy of Sciences, the European Research Council (ERC AdG 695214 GameofGates, to E.G. and G.F.), the Austrian Science Fund (FWF I2192-B22 ERASE, to A.C.-R.; FWF P29250-B30 VITRA, to E.G., J.K. and G.F.) and also a Marie Sklodowska-Curie fellowship to E.G. (MSCA-IF-2014-661491). Research in the Kubicek laboratory is supported by the Austrian Federal Ministry for Digital and Economic Affairs and the National Foundation for Research, Technology and Development, the Austrian Science Fund (FWF) F4701 and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (ERC-CoG-772437). The Pharmacoinformatics Research Group (Ecker lab) acknowledges funding provided by the Austrian Science Fund FWF AW012321 MolTag.
C.-H.L. is an employee of AstraZeneca Limited (UK). The other authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Girardi, E., César-Razquin, A., Lindinger, S. et al. A widespread role for SLC transmembrane transporters in resistance to cytotoxic drugs. Nat Chem Biol 16, 469–478 (2020). https://doi.org/10.1038/s41589-020-0483-3
Nature Chemical Biology (2020)