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    Histone deacetylase activity mediates acquired resistance towards structurally diverse HSP90 inhibitors

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    Author
    Chai, RC; Vieusseux, JL; Lang, BJ; Nguyen, CH; Kouspou, MM; Britt, KL; Price, JT
    Date
    2017-05-01
    Source Title
    Molecular Oncology
    Publisher
    WILEY
    University of Melbourne Author/s
    Britt, Kara; Price, John
    Affiliation
    Sir Peter MacCallum Department of Oncology
    Medicine and Radiology
    Metadata
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    Document Type
    Journal Article
    Citations
    Chai, R. C., Vieusseux, J. L., Lang, B. J., Nguyen, C. H., Kouspou, M. M., Britt, K. L. & Price, J. T. (2017). Histone deacetylase activity mediates acquired resistance towards structurally diverse HSP90 inhibitors. MOLECULAR ONCOLOGY, 11 (5), pp.567-583. https://doi.org/10.1002/1878-0261.12054.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/258421
    DOI
    10.1002/1878-0261.12054
    Abstract
    Heat shock protein 90 (HSP90) regulates multiple signalling pathways critical for tumour growth. As such, HSP90 inhibitors have been shown to act as effective anticancer agents in preclinical studies but, for a number of reasons, the same effect has not been observed in the clinical trials to date. One potential reason for this may be the presence of de novo or acquired resistance within the tumours. To investigate mechanisms of resistance, we generated resistant cell lines through gradual dose escalation of the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG). The resultant resistant cell lines maintained their respective levels of resistance (7-240×) in the absence of 17-AAG and were also cross-resistant with other benzoquinone ansamycin HSP90 inhibitors. Expression of members of the histone deacetylase family (HDAC 1, 5, 6) was altered in the resistant cells. To determine whether HDAC activity contributed to resistance, pan-HDAC inhibitors (TSA and LBH589) and the class II HDAC-specific inhibitor SNDX275 were found to resensitize resistant cells towards 17-AAG and 17-dimethylaminoethylamino-17-demethoxygeldanamycin. Most significantly, resistant cells were also identified as cross-resistant towards structurally distinct HSP90 inhibitors such as radicicol and the second-generation HSP90 inhibitors CCT018159, VER50589 and AUY922. HDAC inhibition also resensitized resistant cells towards these classes of HSP90 inhibitors. In conclusion, we report that prolonged 17-AAG treatment results in acquired resistance of cancer cells towards not just 17-AAG but also to a spectrum of structurally distinct HSP90 inhibitors. This acquired resistance can be inhibited using clinically relevant HDAC inhibitors. This work supports the potential benefit of using HSP90 and HDAC inhibitors in combination within the clinical setting.

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