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Reply to: Ricolinostat is not a highly selective HDAC6 inhibitor

Nature Cancer volume 4, pages 809–811 (2023)Cite this article

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The Original Article was published on 15 June 2023

replying to G. Médard & J. M. Sheltzer Nature Cancer https://doi.org/10.1038/s43018-023-00582-3 (2023)

In their letter1, Médard and Sheltzer express concern regarding potential off-target effects and associated toxicity when using the HDAC6 inhibitor ricolinostat as anticancer therapy. This is based on some results that use genetically engineered HDAC6-knockout cells. We would like to discuss the interpretation of these results as well as additional information regarding the specific targeting of HDAC6 in different cancer settings and the lack of toxicity observed with ricolinostat when treating patients.

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References

  1. Visvader, J. E. & Lindeman, G. J. Mammary stem cells and mammopoiesis. Cancer Res. 66, 9798–9801 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Depetter, Y. et al. Selective pharmacological inhibitors of HDAC6 reveal biochemical activity but functional tolerance in cancer models. Int. J. Cancer 145, 735–747 (2019).

    Article  CAS  PubMed  Google Scholar 

  3. Winkler, R. et al. Targeting the MYC interaction network in B-cell lymphoma via histone deacetylase 6 inhibition. Oncogene 41, 4560–4572 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Lin, A. et al. Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials. Sci. Transl. Med. 11, eaaw8412 (2019).

  5. Teng, X. et al. Genome-wide consequences of deleting any single gene. Mol. Cell 52, 485–494 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zeleke, T. Z. et al. Network-based assessment of HDAC6 activity predicts preclinical and clinical responses to the HDAC6 inhibitor ricolinostat in breast cancer. Nat. Cancer 4, 257–275 (2023).

    Article  CAS  PubMed  Google Scholar 

  7. Sharif, T. et al. HDAC6 differentially regulates autophagy in stem-like versus differentiated cancer cells. Autophagy 15, 686–706 (2019).

    Article  CAS  PubMed  Google Scholar 

  8. Dowling, C. M. et al. Multiple screening approaches reveal HDAC6 as a novel regulator of glycolytic metabolism in triple-negative breast cancer. Sci. Adv. 7, eabc4897 (2021).

  9. Hao, L. et al. Limited agreement of independent RNAi screens for virus-required host genes owes more to false-negative than false-positive factors. PLoS Comput. Biol. 9, e1003235 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Dede, M., Kim, E. & Hart, T. Biases and blind-spots in genome-wide CRISPR knockout screens. Preprint at bioRxiv https://doi.org/10.1101/2020.01.16.909606 (2020).

  11. Namdar, M., Perez, G., Ngo, L. & Marks, P. A. Selective inhibition of histone deacetylase 6 (HDAC6) induces DNA damage and sensitizes transformed cells to anticancer agents. Proc. Natl Acad. Sci. USA 107, 20003–20008 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bai, J., Lei, Y., An, G. L. & He, L. Down-regulation of deacetylase HDAC6 inhibits the melanoma cell line A375.S2 growth through ROS-dependent mitochondrial pathway. PLoS ONE 10, e0121247 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Lechner, S. et al. Target deconvolution of HDAC pharmacopoeia reveals MBLAC2 as common off-target. Nat. Chem. Biol. 18, 812–820 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Santo, L. et al. Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma. Blood 119, 2579–2589 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lee, E. K. et al. Results of an abbreviated phase Ib study of the HDAC6 inhibitor ricolinostat and paclitaxel in recurrent ovarian, fallopian tube, or primary peritoneal cancer. Gynecol. Oncol. Rep. 29, 118–122 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Vogl, D. T. et al. Ricolinostat, the first selective histone deacetylase 6 inhibitor, in combination with bortezomib and dexamethasone for relapsed or refractory multiple myeloma. Clin. Cancer Res. 23, 3307–3315 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Amengual, J. E. et al. First-in-class selective HDAC6 inhibitor (ACY-1215) has a highly favorable safety profile in patients with relapsed and refractory lymphoma. Oncologist 26, 184–e366 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhang, J., Ma, J., Trinh, R. T., Heijnen, C. J. & Kavelaars, A. An HDAC6 inhibitor reverses chemotherapy-induced mechanical hypersensitivity via an IL-10 and macrophage dependent pathway. Brain Behav. Immun. 100, 287–296 (2022).

    Article  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Pathology, Icahn School of Medicine at Mount Sinai Hospital, New York, NY, USA

    Jose Silva

  2. Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Jiyang Yu

  3. Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA

    Kevin Kalinsky

Authors
  1. Jose Silva
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  2. Jiyang Yu
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  3. Kevin Kalinsky
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All authors contributed equally in all aspect of the design, writing and editing of this paper.

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Correspondence to Jose Silva.

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The authors declare no competing interests.

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Nature Cancer thanks the anonymous reviewers for their contribution to the peer review of this work.

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Silva, J., Yu, J. & Kalinsky, K. Reply to: Ricolinostat is not a highly selective HDAC6 inhibitor. Nat Cancer 4, 809–811 (2023). https://doi.org/10.1038/s43018-023-00583-2

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