Using transcriptome sequencing to identify mechanisms of drug action and resistance (original) (raw)

Nature Chemical Biology volume 8, pages 235–237 (2012)Cite this article

Subjects

Abstract

Determining mechanisms of drug action in human cells remains a major challenge. Here we describe an approach in which multiple-drug-resistant clones are isolated and transcriptome sequencing is used to find mutations in each clone. Further analysis of mutations common to more than one clone can identify a drug's physiological target and indirect resistance mechanisms, as indicated by our proof-of-concept studies of the cytotoxic anticancer drugs BI 2536 and bortezomib.

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

Access options

Subscribe to this journal

Receive 12 print issues and online access

$259.00 per year

only $21.58 per issue

Buy this article

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

Additional access options:

Similar content being viewed by others

References

  1. Chan, J.N., Nislow, C. & Emili, A. Trends Pharmacol. Sci. 31, 82–88 (2010).
    Article CAS Google Scholar
  2. Giaever, G. et al. Nat. Genet. 21, 278–283 (1999).
    Article CAS Google Scholar
  3. Ho, C.H. et al. Nat. Biotechnol. 27, 369–377 (2009).
    Article CAS Google Scholar
  4. Walker, G.M. J. Gen. Microbiol. 128, 61–71 (1982).
    CAS PubMed Google Scholar
  5. Ong, S.E. et al. Proc. Natl. Acad. Sci. USA 106, 4617–4622 (2009).
    Article CAS Google Scholar
  6. Rix, U. & Superti-Furga, G. Nat. Chem. Biol. 5, 616–624 (2009).
    Article CAS Google Scholar
  7. Weiss, W.A., Taylor, S.S. & Shokat, K.M. Nat. Chem. Biol. 3, 739–744 (2007).
    Article CAS Google Scholar
  8. Gorre, M.E. et al. Science 293, 876–880 (2001).
    CAS Google Scholar
  9. Azam, M., Latek, R.R. & Daley, G.Q. Cell 112, 831–843 (2003).
    Article CAS Google Scholar
  10. Lénárt, P. et al. Curr. Biol. 17, 304–315 (2007).
    Article Google Scholar
  11. Teraishi, F. et al. Cancer Res. 65, 6380–6387 (2005).
    Article CAS Google Scholar
  12. Glaab, W.E. & Tindall, K.R. Carcinogenesis 18, 1–8 (1997).
    Article CAS Google Scholar
  13. Girdler, F. et al. Chem. Biol. 15, 552–562 (2008).
    Article CAS Google Scholar
  14. Kothe, M. et al. Chem. Biol. Drug Des. 70, 540–546 (2007).
    Article CAS Google Scholar
  15. Scutt, P.J. et al. J. Biol. Chem. 284, 15880–15893 (2009).
    Article CAS Google Scholar
  16. Yusuf, R.Z., Duan, Z., Lamendola, D.E., Penson, R.T. & Seiden, M.V. Curr. Cancer Drug Targets 3, 1–19 (2003).
    Article CAS Google Scholar
  17. Chen, D., Frezza, M., Schmitt, S., Kanwar, J. & Dou, Q.P. Curr. Cancer Drug Targets 11, 239–253 (2011).
    Article CAS Google Scholar
  18. Lü, S. et al. J. Pharmacol. Exp. Ther. 326, 423–431 (2008).
    Article Google Scholar
  19. Oerlemans, R. et al. Blood 112, 2489–2499 (2008).
    Article CAS Google Scholar
  20. Groll, M., Berkers, C.R., Ploegh, H.L. & Ovaa, H. Structure 14, 451–456 (2006).
    Article CAS Google Scholar
  21. Skoufias, D.A. et al. J. Biol. Chem. 281, 17559–17569 (2006).
    Article CAS Google Scholar
  22. Rickert, K.W. et al. Arch. Biochem. Biophys. 469, 220–231 (2008).
    Article CAS Google Scholar
  23. Wood, K.W. et al. Proc. Natl. Acad. Sci. USA 107, 5839–5844 (2010).
    Article CAS Google Scholar

Download references

Acknowledgements

We thank the Genomics Resources Core Facility of Weill Cornell Medical College for conducting the RNA-seq and D. Soong (Weill Cornell Medical College) for providing custom analysis software. This work was supported by the US National Science Foundation CAREER grant 1054964 (O.E.) and US National Institutes of Health GM98579 and GM65933 (T.M.K.).

Author information

Authors and Affiliations

  1. Laboratory of Chemistry and Cell Biology, The Rockefeller University, New York, New York, USA
    Sarah A Wacker, Benjamin R Houghtaling & Tarun M Kapoor
  2. Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York, USA
    Olivier Elemento

Authors

  1. Sarah A Wacker
    You can also search for this author inPubMed Google Scholar
  2. Benjamin R Houghtaling
    You can also search for this author inPubMed Google Scholar
  3. Olivier Elemento
    You can also search for this author inPubMed Google Scholar
  4. Tarun M Kapoor
    You can also search for this author inPubMed Google Scholar

Contributions

S.A.W. carried out all experiments other than the selection of BI 2536–resistant clones, which was done by B.R.H. O.E. conducted bioinformatics analysis. T.M.K. conceived the project, and T.M.K. and O.E. directed the project.

Corresponding authors

Correspondence toOlivier Elemento or Tarun M Kapoor.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Methods and Supplementary Results (PDF 782 kb)

Supplementary Dataset 1

Upregulated Genes in BI 2536-resistant Clones, values are log2 ratios between clone RPKM and HCT-116 RPKM (XLS 93 kb)

Supplementary Dataset 2

Downregulated Genes in BI 2536-resistant Clones, values are log2 ratios between clone RPKM and HCT-116 RPKM (XLS 89 kb)

Supplementary Dataset 3

Upregulated Genes in Bortezomib-resistant Clones, values are log2 ratios between clone RPKM and HCT-116 RPKM (XLS 182 kb)

Supplementary Dataset 4

Downregulated Genes in Bortezomib-resistant Clones, values are log2 ratios between clone RPKM and HCT-116 RPKM (XLS 148 kb)

Rights and permissions

About this article

Cite this article

Wacker, S., Houghtaling, B., Elemento, O. et al. Using transcriptome sequencing to identify mechanisms of drug action and resistance.Nat Chem Biol 8, 235–237 (2012). https://doi.org/10.1038/nchembio.779

Download citation

This article is cited by