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A widespread role for SLC transmembrane transporters in resistance to cytotoxic drugs

Nature Chemical Biology volume 16, pages 469–478 (2020)Cite this article

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Abstract

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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Fig. 1: Experimental setup and overview of the screened compound set.
Fig. 2: Identification of enriched SLCs upon compound treatment.
Fig. 3: Validation of a set of SLC/compound associations by multicolor competition assay (MCA).
Fig. 4: Characterization of selected SLC/drug associations.
Fig. 5: Chemoinformatic analysis of the compound subsets employed in this study.

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Data availability

The data and code that support the findings of this study are available on request from the corresponding author. Data used to generate Figs. 2c and 3b and Supplementary Fig. 3b are available in Supplementary Datasets 1 and 2.

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Acknowledgements

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.

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  1. Konstantinos Papakostas

    Present address: ViruSure GmbH, Tech Gate Vienna, Vienna, Austria

Authors and Affiliations

  1. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria

    Enrico Girardi, Adrián César-Razquin, Sabrina Lindinger, Konstantinos Papakostas, Justyna Konecka, Felix Kartnig, Bettina Gürtl, Kristaps Klavins, Vitaly Sedlyarov, Alvaro Ingles-Prieto, Giuseppe Fiume, Anna Koren, Charles-Hugues Lardeau, Richard Kumaran Kandasamy, Stefan Kubicek & Giulio Superti-Furga

  2. Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria

    Jennifer Hemmerich, Stefanie Kickinger & Gerhard F. Ecker

  3. Christian Doppler Laboratory for Chemical Epigenetics and Antiinfectives, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria

    Anna Koren, Charles-Hugues Lardeau & Stefan Kubicek

  4. Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway

    Richard Kumaran Kandasamy

  5. Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria

    Giulio Superti-Furga

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Contributions

E.G., G.S.-F. conceived and designed the study. E.G., K.P., S.L., J.K., B.G., K.K., G.F., A.I.-P., F.K., A.K. and C.-H.L. performed experiments and analyzed data. A.C.-R. analyzed screening and validation data. V.S. analyzed the transcriptomics data. J.H., S. Kickinger and G.F.E. performed the chemoinformatic analysis. R.K.K. contributed to library design. S. Kubicek, G.F.E. and G.S.-F. provided supervision.

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Correspondence to Giulio Superti-Furga.

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C.-H.L. is an employee of AstraZeneca Limited (UK). The other authors declare no competing interests.

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Supplementary information

Supplementary Information

Supplementary Tables 1–5 and Figs. 1–6.

Reporting Summary

Supplementary Dataset 1

P and FDR values used to generate Fig. 2c.

Supplementary Dataset 2

Ratios and P values used to generate Fig. 3b and Supplementary Fig. 3b.

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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

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