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Myeloma

Signalling profile and antitumour activity of the novel Hsp90 inhibitor NVP-AUY922 in multiple myeloma

Leukemia volume 22, pages 1604–1612 (2008)Cite this article

Abstract

We as well as others have recently shown that Hsp90 is overexpressed in multiple myeloma (MM) and critically contributes to tumour cell survival. Pharmacologic blockade of Hsp90 has consistently been found to induce MM cell death. However, most data have been obtained with MM cell lines whereas knowledge about the molecular effects of pharmacologic Hsp90 blockade in primary tumour cells is limited. Furthermore, these investigations have so far focused on geldanamycin derivatives. We analysed the biochemical effects of a novel diarylisoxazole-based Hsp90 inhibitor (NVP-AUY922) on signalling pathways and cell death in a large set of primary MM tumour samples and in MM cell lines. Treated cells displayed the molecular signature and pharmacodynamic properties for abrogation of Hsp90 function, such as downregulation of multiple survival pathways and strong upregulation of Hsp70. NVP-AUY922 treatment efficiently induced MM cell apoptosis and revealed both sensitive and resistant subgroups. Sensitivity was not correlated with TP53 mutation or Hsp70 induction levels and stromal cells from the bone marrow microenvironment were unable to abrogate NVP-AUY922-induced apoptosis of MM cells. Thus, NVP-AUY922 may be a promising drug for treatment of MM and clinical studies are warranted.

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Acknowledgements

This work was supported in parts by grants from the Deutsche Forschungsgemeinschaft (SFB-TR17/C5), the Deutsche Krebshilfe (grant no. 107715) and the Deutsche José Carreras Leukämie-Stiftung e. V. (grant no. R06/17).

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Authors and Affiliations

  1. Department of Internal Medicine II, Division of Hematology, University Hospital Würzburg, Würzburg, Germany

    T Stühmer, A Zöllinger, M Chatterjee, E Grella, S Knop, M Kortüm, C Unzicker, H Einsele & R C Bargou

  2. Department of Molecular Internal Medicine, Division of Hematology, University Hospital Würzburg, Würzburg, Germany

    D Siegmund & H Wajant

  3. Oncology Research, Novartis Institutes for BioMedical Research, Basel, Switzerland

    M R Jensen, P Chène, J Schoepfer & C García-Echeverría

  4. Exploratory Clinical Development Oncology, Novartis Pharma AG, Basel, Switzerland

    C Quadt

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  1. T Stühmer
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Correspondence to T Stühmer.

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Stühmer, T., Zöllinger, A., Siegmund, D. et al. Signalling profile and antitumour activity of the novel Hsp90 inhibitor NVP-AUY922 in multiple myeloma. Leukemia 22, 1604–1612 (2008). https://doi.org/10.1038/leu.2008.111

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