Resistance to histone deacetylase inhibitors confers hypersensitivity to oncolytic reovirus therapy
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Univ Arizona, Div Translat & Regenerat Med, Dept Med, Canc CtrUniv Arizona, Dept Med, Div Hematol & Oncol, Canc Ctr
Issue Date
2020-10-27
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AMER SOC HEMATOLOGYCitation
Islam, S., Espitia, C. M., Persky, D. O., Carew, J. S., & Nawrocki, S. T. (2020). Resistance to histone deacetylase inhibitors confers hypersensitivity to oncolytic reovirus therapy. Blood Advances, 4(20), 5297-5310.Journal
BLOOD ADVANCESRights
© 2020 by The American Society of Hematology.Collection Information
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.Abstract
Despite the promising antilymphoma activity of histone deacetylase (HDAC) inhibitors as a drug class, resistance is a significant clinical issue. Elucidating the molecular mechanisms drivingHDACinhibitor resistance and/or the specific targets that are altered in drug-resistant cells may facilitate the development of strategies that overcome drug resistance and are more effective for refractory patients. We generated novel T-cell lymphoma (TCL) cell line models of acquired resistance to the HDAC inhibitor belinostat to identify potential effective therapies. Belinostat-resistant cells displayed significant cross-resistance to other HDAC inhibitors including romidepsin, panobinostat, and vorinostat. Consistent with a lack of sensitivity to HDAC inhibitors, the resistant cells failed to induce increased acetylated histones. Drug-resistant cells featured significantly decreased expression of the key antiviral mediators IRF1 and STAT1. On the basis of these findings, we investigated the efficacy of the clinical formulation of reovirus (Reolysin) in parental and drug-resistant models. Our investigation revealed that HDAC inhibitor-resistant cells displayed enhanced vulnerability to reovirus replication and cell death in both in vitro and in vivo models compared with their parental counterparts. Importantly, Reolysin also significantly increased the antilymphoma activity of belinostat in HDAC inhibitor-resistant cells. Our data demonstrate that Reolysin alone or in combination with belinostat is a novel therapeutic strategy to treat TCL patients who develop resistance to HDAC inhibitors.ISSN
2473-9529EISSN
2473-9537PubMed ID
33108458Version
Final published versionae974a485f413a2113503eed53cd6c53
10.1182/bloodadvances.2020002297
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