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

// Jodie F. Hay 1, 2 , Katrina Lappin 1 , Fabio Liberante 1, 3 , Laura M. Kettyle 1, 4 , Kyle B. Matchett 1 , Alexander Thompson 1, 5 and Ken I. Mills 1 1 Blood Cancer Research Group, Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast, UK 2 Molecular Oncology Laboratory, MRC – University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, UK 3 Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria 4 Haematopoietic Stem Cell Biology, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK 5 Division of Cancer and Stem Cells, Centre for Biomolecular Sciences, University of Nottingham, Nottingham, UK Correspondence to: Ken I. Mills, email: k.mills@qub.ac.uk Keywords: acute myeloid leukaemia, Vorinostat, HDAC, epigenetics Received: October 15, 2016     Accepted: May 31, 2017     Published: July 01, 2017 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.