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Paralog-selective Hsp90 inhibitors define tumor-specific regulation of HER2

Nature Chemical Biology volume 9, pages 677–684 (2013)Cite this article

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Abstract

Although the Hsp90 chaperone family, comprised in humans of four paralogs, Hsp90α, Hsp90β, Grp94 and Trap-1, has important roles in malignancy, the contribution of each paralog to the cancer phenotype is poorly understood. This is in large part because reagents to study paralog-specific functions in cancer cells have been unavailable. Here we combine compound library screening with structural and computational analyses to identify purine-based chemical tools that are specific for Hsp90 paralogs. We show that Grp94 selectivity is due to the insertion of these compounds into a new allosteric pocket. We use these tools to demonstrate that cancer cells use individual Hsp90 paralogs to regulate a client protein in a tumor-specific manner and in response to proteome alterations. Finally, we provide new mechanistic evidence explaining why selective Grp94 inhibition is particularly efficacious in certain breast cancers.

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Figure 1: Library screening identifies paralog specific chemical spaces.
Figure 2: Structural and computational analyses define differences in Hsp90 paralog pockets and paralog-selective chemical spaces.
Figure 3: HER2 is sensitive to Hsp90 paralog inhibition in a tumor-specific manner.
Figure 4: Grp94 and Hsp90α and Hsp90β regulate distinct HER2 functions in HER2-overexpressing cancer cells.
Figure 5: Schematic representation summarizing the tumor-specific regulation of HER2 by the Hsp90 paralogs.
Figure 6: Grp94 inhibition alone is sufficient to induce apoptosis in and reduce the viability of HER2 overexpressing breast cancer cells.

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Acknowledgements

G.C. is funded by the Breast Cancer Research Fund, R01 CA172546-01A1, U01 AG032969-01A1, R21 AI090501, R21 CA158609-01 and R01 CA155226-01. P.Y. is supported by the Translational and Integrative Medicine Research Fund of Memorial Sloan-Kettering Cancer Center. P.D.P. and R.A.S. are supported by funds and resources from St. John's University. D.T.G. is funded by R01 CA095130. We thank Y. Argon (Children's Hospital of Philadelphia) and C. Leifer (Cornell University College of Veterinary Medicine) for reagents.

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  1. Pallav D Patel, Pengrong Yan, Paul M Seidler and Hardik J Patel: These authors contributed equally to this work.

Authors and Affiliations

  1. Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, New York, USA

    Pallav D Patel, Pengrong Yan, Hardik J Patel, Weilin Sun, Chenghua Yang, Tony Taldone & Gabriela Chiosis

  2. Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, New York, USA

    Pallav D Patel & Ralph A Stephani

  3. Hauptman-Woodward Medical Research Institute, State University of New York, Buffalo, New York, USA

    Paul M Seidler, Nanette S Que & Daniel T Gewirth

  4. Department of Structural Biology, State University of New York, Buffalo, New York, USA

    Paul M Seidler, Nanette S Que & Daniel T Gewirth

  5. Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy

    Paola Finotti

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Contributions

P.D.P., P.Y., H.J.P. and C.Y. performed the chemistry and chemical biology experiments, and T.T. and W.S. provided reagents. P.M.S., N.S.Q. and D.T.G. carried out the crystal structure determination and analysis. All of the authors participated in the design and analysis of various experiments, and G.C., D.T.G. and P.D.P. wrote the paper.

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Correspondence to Daniel T Gewirth or Gabriela Chiosis.

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Competing interests

Memorial Sloan-Kettering Cancer Center holds the intellectual rights to the purine-scaffold Hsp90 inhibitors. Samus Therapeutics, of which G.C. has partial ownership, has licensed PU-H71.

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Patel, P., Yan, P., Seidler, P. et al. Paralog-selective Hsp90 inhibitors define tumor-specific regulation of HER2. Nat Chem Biol 9, 677–684 (2013). https://doi.org/10.1038/nchembio.1335

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