PT - JOURNAL ARTICLE AU - Christine R Klaus AU - Dorothy Iwanowicz AU - L. Danielle Johnston AU - Carly A Campbell AU - Jesse J Smith AU - Mikel P Moyer AU - Robert A Copeland AU - Edward J Olhava AU - Margaret Porter Scott AU - Roy M Pollock AU - Scott R Daigle AU - Alejandra Raimondi TI - DOT1L Inhibitor EPZ-5676 Displays Synergistic Antiproliferative Activity in Combination with Standard of Care Drugs and Hypomethylating Agents in <em>MLL</em>-Rearranged Leukemia Cells AID - 10.1124/jpet.114.214577 DP - 2014 Jan 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - jpet.114.214577 4099 - http://jpet.aspetjournals.org/content/early/2014/07/03/jpet.114.214577.short 4100 - http://jpet.aspetjournals.org/content/early/2014/07/03/jpet.114.214577.full AB - EPZ-5676, a small molecule inhibitor of the protein methyltransferase DOT1L, is currently under clinical investigation for acute leukemias bearing MLL-rearrangements (MLL-r). In this study, we evaluated EPZ-5676 in combination with standard of care (SOC) agents for acute leukemias as well as other chromatin modifying drugs in cellular assays with three human acute leukemia cell lines MOLM-13 (MLL-AF9), MV4-11 (MLL-AF4) and SKM-1 (non-MLL-r). Studies were performed to evaluate the anti-proliferative effects of EPZ-5676 combinations in a co-treatment model where the second agent was added simultaneously with EPZ-5676 at the beginning of the assay or, in a pre-treatment model where cells were incubated for several days in the presence of EPZ-5676 prior to the addition of the second agent. EPZ-5676 was found to act synergistically with the acute myeloid leukemia (AML) SOC agents, cytarabine or daunorubicin in MOLM-13 and MV4-11 MLL-r cell lines. EPZ-5676 is selective for MLL-r cell lines as demonstrated by its lack of effect either alone or in combination in the non-rearranged SKM-1 cell line. In MLL-r cells, the combination benefit was observed even when EPZ-5676 was washed out prior to the addition of the chemotherapeutic agents, suggesting that EPZ-5676 sets up a durable, altered chromatin state that enhances the chemotherapeutic effects. Our evaluation of EPZ-5676 in conjunction with other chromatin modifying drugs also revealed a consistent combination benefit including synergy with DNA hypomethylating agents. These results indicate that EPZ-5676 is highly efficacious as a single agent and synergistically acts with other chemotherapeutics including AML SOC drugs and DNA hypomethylating agents in MLL-r cells.