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ATP-competitive inhibitors block protein kinase recruitment to the Hsp90-Cdc37 system

Nature Chemical Biology volume 9, pages 307–312 (2013)Cite this article

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A Corrigendum to this article was published on 20 May 2013

Abstract

Protein kinase clients are recruited to the Hsp90 molecular chaperone system via Cdc37, which simultaneously binds Hsp90 and kinases and regulates the Hsp90 chaperone cycle. Pharmacological inhibition of Hsp90 in vivo results in degradation of kinase clients, with a therapeutic effect in dependent tumors. We show here that Cdc37 directly antagonizes ATP binding to client kinases, suggesting a role for the Hsp90–Cdc37 complex in controlling kinase activity. Unexpectedly, we find that Cdc37 binding to protein kinases is itself antagonized by ATP-competitive kinase inhibitors, including vemurafenib and lapatinib. In cancer cells, these inhibitors deprive oncogenic kinases such as B-Raf and ErbB2 of access to the Hsp90–Cdc37 complex, leading to their degradation. Our results suggest that at least part of the efficacy of ATP-competitive inhibitors of Hsp90-dependent kinases in tumor cells may be due to targeted chaperone deprivation.

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Figure 1: The B-Raf catalytic domain associates with Cdc37–Hsp90.
Figure 2: Cdc37 antagonizes nucleotide binding to B-Raf.
Figure 3: ATP-competitive inhibitors antagonize Cdc37 binding to kinases.
Figure 4: Kinase inhibitors prevent association with Cdc37–Hsp90 in human tumor cells.
Figure 5: Manipulation of Cdc37 amounts alters sensitivity of HT29 human colon cancer cells to growth inhibition by vemurafenib.

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Acknowledgements

We are grateful to L. Zhou (University of Sussex) for assistance with insect cell expression; to R.M.L. Morgan and S. Parry-Morris (both from University of Sussex) for provision of Hsp90 and Mek1 protein; S.H. Millson (University of Sheffield) for provision of Cak1p-containing pellets; J.R. Smith (The Institute of Cancer Research) for Cdc37 knockdown and overexpressing cell lines; and to A.W. Oliver and S.M. Roe (both from University of Sussex) for useful discussions. P.W., P.A.C. and R.S.S. acknowledge funding from the UK National Health Service to the National Institute for Health Research Biomedical Research Centre at The Institute of Cancer Research and Royal Marsden Hospital. L.H.P. acknowledges funding for the Genome Damage and Stability Centre from the Medical Research Council. This work was supported by Cancer Research UK Programme grant C309/A8274 (P.W.), a European Molecular Biology Organization Long-Term Fellowship (S.P.) and a Wellcome Trust Senior Investigator Award (095605/Z/11/Z to L.H.P.). P.W. is a Cancer Research UK Life Fellow.

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Authors and Affiliations

  1. Medical Research Council Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, UK

    Sigrun Polier, Chrisostomos Prodromou & Laurence H Pearl

  2. Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, UK

    Rahul S Samant, Paul A Clarke & Paul Workman

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  1. Sigrun Polier
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Contributions

S.P. designed the study, performed the in vitro experiments, analyzed the data, prepared the figures and coauthored the manuscript. R.S.S. and P.A.C. performed the in vivo experiments and analyzed the data. P.W. designed the study, analyzed the data and coauthored the manuscript. C.P. designed the study, performed in vitro experiments and analyzed the data. L.H.P. designed the study, analyzed the data, prepared the figures and coauthored the manuscript. All authors commented on the manuscript.

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Correspondence to Sigrun Polier, Paul Workman or Laurence H Pearl.

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Polier, S., Samant, R., Clarke, P. et al. ATP-competitive inhibitors block protein kinase recruitment to the Hsp90-Cdc37 system. Nat Chem Biol 9, 307–312 (2013). https://doi.org/10.1038/nchembio.1212

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