ARID1B is a specific vulnerability in ARID1A-mutant cancers

Abstract

Recent studies have revealed that ARID1A, encoding AT-rich interactive domain 1A (SWI-like), is frequently mutated across a variety of human cancers and also has bona fide tumor suppressor properties. Consequently, identification of vulnerabilities conferred by ARID1A mutation would have major relevance for human cancer. Here, using a broad screening approach, we identify ARID1B, an ARID1A homolog whose gene product is mutually exclusive with ARID1A in SWI/SNF complexes, as the number 1 gene preferentially required for the survival of ARID1A-mutant cancer cell lines. We show that loss of ARID1B in ARID1A-deficient backgrounds destabilizes SWI/SNF and impairs proliferation in both cancer cells and primary cells. We also find that ARID1A and ARID1B are frequently co-mutated in cancer but that ARID1A-deficient cancers retain at least one functional ARID1B allele. These results suggest that loss of ARID1A and ARID1B alleles cooperatively promotes cancer formation but also results in a unique functional dependence. The results further identify ARID1B as a potential therapeutic target for ARID1A-mutant cancers.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: ARID1B is a specific vulnerability in ARID1A-mutant cancer cell lines.
Figure 2: ARID1B is required for the maintenance of an intact SWI/SNF complex in ARID1A-mutant cancer cell lines and primary cells.

References

  1. 1

    Cheung, H.W. et al. Proc. Natl. Acad. Sci. USA 108, 12372–12377 (2011).

    CAS  Article  Google Scholar 

  2. 2

    Shao, D.D. et al. Genome Res. 23, 665–678 (2013).

    CAS  Article  Google Scholar 

  3. 3

    Wu, J.N. & Roberts, C.W. Cancer Discov. 3, 35–43 (2013).

    CAS  Article  Google Scholar 

  4. 4

    Ryme, J., Asp, P., Bohm, S., Cavellan, E. & Farrants, A.K. J. Cell. Biochem. 108, 565–576 (2009).

    CAS  Article  Google Scholar 

  5. 5

    Tolstorukov, M.Y. et al. Proc. Natl. Acad. Sci. USA 110, 10165–10170 (2013).

    CAS  Article  Google Scholar 

  6. 6

    Klochendler-Yeivin, A. et al. EMBO Rep. 1, 500–506 (2000).

    CAS  Article  Google Scholar 

  7. 7

    Bultman, S. et al. Mol. Cell 6, 1287–1295 (2000).

    CAS  Article  Google Scholar 

  8. 8

    Kim, J.K. et al. Mol. Cell. Biol. 21, 7787–7795 (2001).

    CAS  Article  Google Scholar 

  9. 9

    Roberts, C.W., Leroux, M.M., Fleming, M.D. & Orkin, S.H. Cancer Cell 2, 415–425 (2002).

    CAS  Article  Google Scholar 

  10. 10

    Gao, X. et al. Proc. Natl. Acad. Sci. USA 105, 6656–6661 (2008).

    CAS  Article  Google Scholar 

  11. 11

    Sausen, M. et al. Nat. Genet. 45, 12–17 (2013).

    CAS  Article  Google Scholar 

  12. 12

    Barretina, J. et al. Nature 483, 603–607 (2012).

    CAS  Article  Google Scholar 

  13. 13

    Cerami, E. et al. Cancer Discov. 2, 401–404 (2012).

    Article  Google Scholar 

  14. 14

    Wang, X. et al. Cancer Res. 69, 8094–8101 (2009).

    CAS  Article  Google Scholar 

  15. 15

    Oike, T. et al. Cancer Res. 73, 5508–5518 (2013).

    CAS  Article  Google Scholar 

  16. 16

    Filippakopoulos, P. et al. Nature 468, 1067–1073 (2010).

    CAS  Article  Google Scholar 

  17. 17

    Oltersdorf, T. et al. Nature 435, 677–681 (2005).

    CAS  Article  Google Scholar 

  18. 18

    Ostrem, J.M., Peters, U., Sos, M.L., Wells, J.A. & Shokat, K.M. Nature 503, 548–551 (2013).

    CAS  Article  Google Scholar 

  19. 19

    Li, X.S., Trojer, P., Matsumura, T., Treisman, J.E. & Tanese, N. Mol. Cell. Biol. 30, 1673–1688 (2010).

    CAS  Article  Google Scholar 

  20. 20

    Kim, W. et al. Nat. Chem. Biol. 9, 643–650 (2013).

    CAS  Article  Google Scholar 

  21. 21

    Isakoff, M.S. et al. Proc. Natl. Acad. Sci. USA 102, 17745–17750 (2005).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank Ping Lu for technical assistance with the setup of the sucrose sedimentation assay. X.W. was supported by a post-doctoral fellowship from David Abraham Foundation and Rally Foundation and a research grant from St. Baldrick's Foundation. B.G.W. was supported by a Childhood Cancer Research Grant from the Pablove Foundation. Z.W. is supported by US National Institutes of Health grant R01HL109054. This work was supported by US National Institutes of Health grants R01CA172152 (C.W.M.R.) and R01CA113794 (C.W.M.R.) and a U01 NCI Mouse Models of Cancer Consortium Award (C.W.M.R.). The Garrett B. Smith Foundation, Miles for Mary and the Cure AT/RT Now foundation (C.W.M.R.) provided additional support.

Author information

Affiliations

Authors

Contributions

C.W.M.R. directed the study. K.C.H. and X.W. designed and performed experiments. J.R.H. and H.E.M. performed experiments. C.W.M.R., K.C.H., X.W., B.G.W., J.R.H., H.E.M. and Z.J. analyzed and interpreted the data. K.C.H., B.G.W., F.V. and A.J.A. analyzed Project Achilles data. G.V.K., M.G. and L.A.G. provided and analyzed sequencing data. Z.W. provided Arid1a-conditional mice, intellectual contribution and useful discussion. Y.K. established the Arid1a-conditional mouse strain. W.C.H. directs the Achilles Project, provided reagents, helped interpret Achilles data and edited the manuscript. C.W.M.R., K.C.H. and X.W. wrote the manuscript.

Corresponding author

Correspondence to Charles W M Roberts.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7, Supplementary Table 1 and Supplementary Discussion (PDF 7122 kb)

Supplementary Data

Supplementary Data (XLSX 498 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Helming, K., Wang, X., Wilson, B. et al. ARID1B is a specific vulnerability in ARID1A-mutant cancers. Nat Med 20, 251–254 (2014). https://doi.org/10.1038/nm.3480

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing