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The solute carrier SLC35F2 enables YM155-mediated DNA damage toxicity


Genotoxic chemotherapy is the most common cancer treatment strategy. However, its untargeted generic DNA-damaging nature and associated systemic cytotoxicity greatly limit its therapeutic applications. Here, we used a haploid genetic screen in human cells to discover an absolute dependency of the clinically evaluated anticancer compound YM155 on solute carrier family member 35 F2 (SLC35F2), an uncharacterized member of the solute carrier protein family that is highly expressed in a variety of human cancers. YM155 generated DNA damage through intercalation, which was contingent on the expression of SLC35F2 and its drug-importing activity. SLC35F2 expression and YM155 sensitivity correlated across a panel of cancer cell lines, and targeted genome editing verified SLC35F2 as the main determinant of YM155-mediated DNA damage toxicity in vitro and in vivo. These findings suggest a new route to targeted DNA damage by exploiting tumor and patient-specific import of YM155.

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Figure 1: Mutagenesis of the SLC35F2 locus confers resistance to YM155.
Figure 2: YM155 induces DNA damage selectively in replicating cells expressing SLC35F2.
Figure 3: Validation of the dependency of YM155 on SLC35F2 using genome editing.
Figure 4: SLC35F2 is a predictive marker for YM155 efficacy in vitro and in vivo.

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We thank all of the members of the Superti-Furga research laboratory and U. Rix (Moffitt Cancer Center) for skillful advice and discussions. The present work was, in part, financed by the Austrian Academy of Sciences (S.K., R.K.K., G.S.-F., D.C. and T.K.); the Gen-AU initiative of the Austrian Federal Ministry for Science, Research and Economy (G.E.W., PLACEBO); the European Commission (B.R., K.V.M.H. and M.G., grant agreement number 259348, ASSET); the European Research Council (R.K.K., grant agreement number 250179, i-FIVE); and the Swiss National Science Foundation (C.T., Fellowship). T.R.B. is funded by the Cancer Genomics Center ( and the Netherlands Organisation for Scientific Research–VIDI grant 91711316. Work in the O.F.-C. laboratory was supported by grants from the Spanish Ministry of Economy and Competitiveness (SAF2011-23753), the Association for International Cancer Research (12-0229), the Howard Hughes Medical Institute and the European Research Council (ERC-617840). C.M.-R. is funded by a PhD fellowship from La Caixa Foundation.

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Authors and Affiliations



G.E.W. designed and performed experiments, analyzed and interpreted the data, made the figures and wrote the manuscript. B.R. designed and performed experiments, interpreted the data and prepared figures. C.M.-R. performed the mouse xenograft experiments, high-content microscopy and the comet assay. V.A.B. helped perform the haploid genetic screen and conducted statistical analysis. C.T. performed the RNA sequencing experiment and helped to perform MRM measurements. R.K.K. analyzed RNA sequencing data and performed statistical analysis. K.V.M.H. helped to set up MRM measurements and gave experimental advice. M.G. assisted with immunoblot analysis. D.C. created the Circos plot and a graphical display of insertion sites. T.K. operated the next-generation sequencer (Illumina HiSeq 2000) and helped with next-generation sequencing data handling. R.K. gave experimental advice and supervised next-generation sequencing. S.K. gave experimental advice and designed experiments. O.F.-C. designed the mouse xenograft study and analyzed and interpreted data. T.R.B. codesigned the study and gave experimental advice. G.S.-F. codesigned and supervised the study and wrote the manuscript.

Corresponding author

Correspondence to Giulio Superti-Furga.

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Competing interests

T.R.B. and G.S.-F. are cofounders and shareholders of Haplogen GmbH, a company involved in haploid genetics.

Supplementary information

Supplementary Text and Figures

Supplementary Results and Supplementary Figures 1–11. (PDF 39594 kb)

Supplementary Table 1

The number of retroviral insertions in genes from YM155-resistant colonies compared to that in control colonies. (XLSX 70 kb)

Supplementary Table 2

Raw data showing transcriptional changes in KBM7WT versus KMB7GT1 cells with 1 μM YM155 treatment. (XLSX 3338 kb)

Supplementary Table 3

Listing of genes and their Pearson's correlation values for YM155 efficacy. (XLSX 1032 kb)

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Winter, G., Radic, B., Mayor-Ruiz, C. et al. The solute carrier SLC35F2 enables YM155-mediated DNA damage toxicity. Nat Chem Biol 10, 768–773 (2014).

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