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Integrated analysis of the molecular action of Vorinostat identifies epi-sensitised targets for combination therapy

Hay, Jodie F.; Lappin, Katrina; Liberante, Fabio; Kettyle, Laura M.; Matchett, Kyle B.; Thompson, Alexander; Mills, Ken I.

Integrated analysis of the molecular action of Vorinostat identifies epi-sensitised targets for combination therapy Thumbnail


Authors

Jodie F. Hay

Katrina Lappin

Fabio Liberante

Laura M. Kettyle

Kyle B. Matchett

Ken I. Mills



Abstract

Several histone deacetylase inhibitors including Vorinostat have received FDA approval for the treatment of haematological malignancies. However, data from these trials indicate that Vorinostat has limited efficacy as a monotherapy, prompting the need for rational design of combination therapies. A number of epi-sensitised pathways, including sonic hedgehog (SHH), were identified in AML cells by integration of global patterns of histone H3 lysine 9 (H3K9) acetylation with transcriptomic analysis following Vorinostat-treatment. Direct targeting of the SHH pathway with SANT-1, following Vorinostat induced epi-sensitisation, resulted in synergistic cell death of AML cells. In addition, xenograft studies demonstrated that combination therapy induced a marked reduction in leukemic burden compared to control or single agents. Together, the data supports epi-sensitisation as a potential component of the strategy for the rational development of combination therapies in AML.

Journal Article Type Article
Acceptance Date May 31, 2017
Online Publication Date Jul 1, 2017
Publication Date Sep 15, 2017
Deposit Date Feb 13, 2018
Publicly Available Date Feb 13, 2018
Journal Oncotarget
Electronic ISSN 1949-2553
Publisher Impact Journals
Peer Reviewed Peer Reviewed
Volume 8
Issue 40
DOI https://doi.org/10.18632/oncotarget.18910
Keywords acute myeloid leukaemia, Vorinostat, HDAC, epigenetics
Public URL https://nottingham-repository.worktribe.com/output/882669
Publisher URL https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620222/

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