Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

The solute carrier SLC35F2 enables YM155-mediated DNA damage toxicity

Nature Chemical Biology volume 10, pages 768–773 (2014)Cite this article

Subjects

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

Accession codes

Primary accessions

ArrayExpress

European Nucleotide Archive

References

  1. Younes, A. et al. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N. Engl. J. Med. 363, 1812–1821 (2010).

    Article  CAS  Google Scholar 

  2. Verma, S. et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N. Engl. J. Med. 367, 1783–1791 (2012).

    Article  CAS  Google Scholar 

  3. Birsoy, K. et al. MCT1-mediated transport of a toxic molecule is an effective strategy for targeting glycolytic tumors. Nat. Genet. 45, 104–108 (2013).

    Article  CAS  Google Scholar 

  4. Reiling, J.H. et al. A haploid genetic screen identifies the major facilitator domain containing 2A (MFSD2A) transporter as a key mediator in the response to tunicamycin. Proc. Natl. Acad. Sci. USA 108, 11756–11765 (2011).

    Article  CAS  Google Scholar 

  5. Lanthaler, K. et al. Genome-wide assessment of the carriers involved in the cellular uptake of drugs: a model system in yeast. BMC Biol. 9, 70 (2011).

    Article  CAS  Google Scholar 

  6. Dobson, P.D. & Kell, D.B. Carrier-mediated cellular uptake of pharmaceutical drugs: an exception or the rule? Nat. Rev. Drug Discov. 7, 205–220 (2008).

    Article  CAS  Google Scholar 

  7. Kell, D.B., Dobson, P.D. & Oliver, S.G. Pharmaceutical drug transport: the issues and the implications that it is essentially carrier-mediated only. Drug Discov. Today 16, 704–714 (2011).

    Article  CAS  Google Scholar 

  8. Giacomini, K.M. et al. Membrane transporters in drug development. Nat. Rev. Drug Discov. 9, 215–236 (2010).

    Article  CAS  Google Scholar 

  9. Tolcher, A.W. et al. Phase I and pharmacokinetic study of YM155, a small-molecule inhibitor of survivin. J. Clin. Oncol. 26, 5198–5203 (2008).

    Article  CAS  Google Scholar 

  10. Giaccone, G. et al. Multicenter phase II trial of YM155, a small-molecule suppressor of survivin, in patients with advanced, refractory, non-small-cell lung cancer. J. Clin. Oncol. 27, 4481–4486 (2009).

    Article  CAS  Google Scholar 

  11. Nakamura, N. et al. Interleukin enhancer-binding factor 3/NF110 is a target of YM155, a suppressant of survivin. Mol. Cell. Proteomics 11, M111.013243 (2012).

    Article  Google Scholar 

  12. Carette, J.E. et al. Haploid genetic screens in human cells identify host factors used by pathogens. Science 326, 1231–1235 (2009).

    Article  CAS  Google Scholar 

  13. Carette, J.E. et al. Global gene disruption in human cells to assign genes to phenotypes by deep sequencing. Nat. Biotechnol. 29, 542–546 (2011).

    Article  CAS  Google Scholar 

  14. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 102, 15545–15550 (2005).

    Article  CAS  Google Scholar 

  15. Glaros, T.G. et al. The “survivin suppressants” NSC 80467 and YM155 induce a DNA damage response. Cancer Chemother. Pharmacol. 70, 207–212 (2012).

    Article  CAS  Google Scholar 

  16. Sappal, D.S. et al. Biological characterization of MLN944: a potent DNA binding agent. Mol. Cancer Ther. 3, 47–58 (2004).

    Article  CAS  Google Scholar 

  17. Cohen, S.N. & Yielding, K.L. Inhibition of DNA and RNA polymerase reactions by chloroquine. Proc. Natl. Acad. Sci. USA 54, 521–527 (1965).

    Article  CAS  Google Scholar 

  18. Bakkenist, C.J. & Kastan, M.B. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421, 499–506 (2003).

    Article  CAS  Google Scholar 

  19. Ishida, N. & Kawakita, M. Molecular physiology and pathology of the nucleotide sugar transporter family (SLC35). Pflugers Arch. 447, 768–775 (2004).

    Article  CAS  Google Scholar 

  20. Song, Z. Roles of the nucleotide sugar transporters (SLC35 family) in health and disease. Mol. Aspects Med. 34, 590–600 (2013).

    Article  CAS  Google Scholar 

  21. Sarangi, A., Bupp, K. & Roth, M.J. Identification of a retroviral receptor used by an envelope protein derived by peptide library screening. Proc. Natl. Acad. Sci. USA 104, 11032–11037 (2007).

    Article  CAS  Google Scholar 

  22. Barretina, J. et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483, 603–607 (2012).

    Article  CAS  Google Scholar 

  23. Cong, L. et al. Multiplex genome engineering using CRISPR/Cas systems. Science 339, 819–823 (2013).

    Article  CAS  Google Scholar 

  24. Mali, P. et al. RNA-guided human genome engineering via Cas9. Science 339, 823–826 (2013).

    Article  CAS  Google Scholar 

  25. Hartwell, L.H., Culotti, J., Pringle, J.R. & Reid, B.J. Genetic control of the cell division cycle in yeast. Science 183, 46–51 (1974).

    Article  CAS  Google Scholar 

  26. Minematsu, T. et al. Carrier-mediated uptake of 1-(2-methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazolium bromide(YM155 monobromide), a novel small-molecule survivin suppressant, into human solid tumor and lymphoma cells. Drug Metab. Dispos. 37, 619–628 (2009).

    Article  CAS  Google Scholar 

  27. Minematsu, T., Iwai, M., Umehara, K., Usui, T. & Kamimura, H. Characterization of human organic cation transporter 1 (OCT1/SLC22A1)- and OCT2 (SLC22A2)-mediated transport of 1-(2-methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazolium bromide (YM155 monobromide), a novel small molecule survivin suppressant. Drug Metab. Dispos. 38, 1–4 (2010).

    Article  CAS  Google Scholar 

  28. Trapnell, C., Pachter, L. & Salzberg, S.L. TopHat: discovering splice junctions with RNA-Seq. Bioinformatics 25, 1105–1111 (2009).

    Article  CAS  Google Scholar 

  29. Langmead, B., Trapnell, C., Pop, M. & Salzberg, S.L. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 10, R25 (2009).

    Article  Google Scholar 

  30. Wang, L., Wang, S. & Li, W. RSeQC: quality control of RNA-seq experiments. Bioinformatics 28, 2184–2185 (2012).

    Article  CAS  Google Scholar 

  31. Wang, L., Feng, Z., Wang, X., Wang, X. & Zhang, X. DEGseq: an R package for identifying differentially expressed genes from RNA-seq data. Bioinformatics 26, 136–138 (2010).

    Article  Google Scholar 

  32. Wang, H. et al. One-step generation of mice carrying mutations in multiple genes by CRISPR/Cas-mediated genome engineering. Cell 153, 910–918 (2013).

    Article  CAS  Google Scholar 

  33. Toledo, L.I., Murga, M., Gutierrez-Martinez, P., Soria, R. & Fernandez-Capetillo, O. ATR signaling can drive cells into senescence in the absence of DNA breaks. Genes Dev. 22, 297–302 (2008).

    Article  CAS  Google Scholar 

  34. Gyori, B.M., Venkatachalam, G., Thiagarajan, P.S., Hsu, D. & Clement, M.V. OpenComet: an automated tool for comet assay image analysis. Redox Biol. 2, 457–465 (2014).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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 (http://www.cancergenomics.nl/) 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.

Author information

Author notes

  1. Branka Radic and Cristina Mayor-Ruiz: These authors contributed equally to this work.

Authors and Affiliations

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

    Georg E Winter, Branka Radic, Claudia Trefzer, Richard K Kandasamy, Kilian V M Huber, Manuela Gridling, Doris Chen, Thorsten Klampfl, Robert Kralovics, Stefan Kubicek, Thijn R Brummelkamp & Giulio Superti-Furga

  2. Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

    Cristina Mayor-Ruiz & Oscar Fernandez-Capetillo

  3. Division of Biochemistry, The Netherlands Cancer Institute, Amsterdam, the Netherlands

    Vincent A Blomen & Thijn R Brummelkamp

Authors
  1. Georg E Winter
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Branka Radic
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cristina Mayor-Ruiz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vincent A Blomen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Claudia Trefzer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Richard K Kandasamy
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kilian V M Huber
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Manuela Gridling
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Doris Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Thorsten Klampfl
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Robert Kralovics
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Stefan Kubicek
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Oscar Fernandez-Capetillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Thijn R Brummelkamp
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Giulio Superti-Furga
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Ethics declarations

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)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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). https://doi.org/10.1038/nchembio.1590

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchembio.1590

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer