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

Nature Chemical Biology
Enrico GirardiGiulio Superti-Furga

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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Citations

Aug 14, 2020·Metallomics : Integrated Biometal Science·Marc J GallenitoGabriele Meloni
Jul 19, 2020·Genome Biology and Evolution·Shane M DeneckeJohn Vontas
Mar 11, 2020·Nature Chemical Biology·Douglas B Kell
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Mar 2, 2021·Angewandte Chemie·George KarageorgisHerbert Waldmann
Apr 4, 2021·Pharmaceuticals·Tyler SniegowskiVadivel Ganapathy
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Jul 27, 2021·Frontiers in Cell and Developmental Biology·Sunday OkutachiDaniel Abankwa
Jul 28, 2021·Pharmacological Reviews·Trevor M PenningTea Lanišnik Rižner
Aug 28, 2021·Frontiers in Pharmacology·Vojtech DvorakGiulio Superti-Furga

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Methods Mentioned

BETA
RNA-seq
FACS
PCA
PCR
FCS
transfection
flow cytometry

Software Mentioned

Rstudio
ggplot2
MassLynx
house
R
dplyr
Rstudio IDE
factoextra
End Sequence Analysis Toolkit ( ESAT )
KNIME

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