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Decitabine-Vorinostat combination treatment in acute myeloid leukemia activates pathways with potential for novel triple therapy

Young, Christine S.; Clarke, Kathryn M.; Kettyle, Laura M.; Thompson, Alexander; Mills, Ken I.

Authors

Christine S. Young

Kathryn M. Clarke

Laura M. Kettyle

Alexander Thompson

Ken I. Mills



Abstract

Despite advancements in cancer therapeutics, acute myeloid leukemia patients over 60 years old have a 5-year survival rate of less than 8%. In an attempt to improve this, epigenetic modifying agents have been combined as therapies in clinical studies. In particular combinations with Decitabine and Vorinostat have had varying degrees of efficacy. This study therefore aimed to understand the underlying molecular mechanisms of these agents to identify potential rational epi-sensitized combinations.

Combined Decitabine-Vorinostat treatment synergistically decreased cell proliferation, induced apoptosis, enhanced acetylation of histones and further decreased DNMT1 protein with HL-60 cells showing a greater sensitivity to the combined treatment than OCI-AML3. Combination therapy led to reprogramming of unique target genes including AXL, a receptor tyrosine kinase associated with cell survival and a poor prognosis in AML, which was significantly upregulated following treatment. Therefore targeting AXL following epi-sensitization with Decitabine and Vorinostat may be a suitable triple combination. To test this, cells were treated with a novel triple combination therapy including BGB324, an AXL specific inhibitor. Triple combination increased the sensitivity of OCI-AML3 cells to Decitabine and Vorinostat as shown through viability assays and significantly extended the survival of mice transplanted with pretreated OCI-AML3 cells, while bioluminescence imaging showed the decrease in disease burden following triple combination treatment.

Further investigation is required to optimize this triple combination, however, these results suggest that AXL is a potential marker of response to Decitabine-Vorinostat combination treatment and offers a new avenue of epigenetic combination therapies for acute myeloid leukemia.

Journal Article Type Article
Publication Date May 19, 2017
Journal Oncotarget
Electronic ISSN 1949-2553
Publisher Impact Journals
Peer Reviewed Peer Reviewed
Volume 8
Issue 31
APA6 Citation Young, C. S., Clarke, K. M., Kettyle, L. M., Thompson, A., & Mills, K. I. (2017). Decitabine-Vorinostat combination treatment in acute myeloid leukemia activates pathways with potential for novel triple therapy. Oncotarget, 8(31), https://doi.org/10.18632/oncotarget.18009
DOI https://doi.org/10.18632/oncotarget.18009
Keywords epigenetic combination therapies, AXL receptor tyrosine kinase, acute myeloid leukemia, HDAC inhibitors, DNMT
inhibitors
Publisher URL https://doi.org/10.18632/oncotarget.18009
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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