EZH2 Inhibitor Efficacy in Non-Hodgkin’s Lymphoma Does Not Require Suppression of H3K27 Monomethylation

Bradley, William D.; Arora, Shilpi; Busby, Jennifer; Balasubramanian, Srividya; Gehling, Victor S.; Nasveschuk, Christopher G.; Vaswani, Rishi G.; Yuan, Chih-Chi; Hatton, Charlie; Zhao, Feng; Williamson, Kaylyn E.; Iyer, Priyadarshini; Méndez, Jacqui; Campbell, Robert M.; Cantone, Nico; Garapaty-Rao, Shivani; Audia, James E.; Cook, Andrew S.; Dakin, Les A.; Albrecht, Brian K.; Harmange, Jean-Christophe; Daniels, Danette L.; Cummings, Richard; Bryant, Barbara M.; Normant, Emmanuel; Trojer, Patrick

doi:10.1016/j.chembiol.2014.09.017

Cited by 132 publications

(129 citation statements)

References 48 publications

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“…BI is a much simpler and straightforward way of measuring interactions than Loewe additivity, which requires examination of interactions across a gradient of concentrations for each of the drugs. Although Loewe integrates more information about interactions, the ease of measurement and calculation of BI has led to its use in a huge number of studies [8,14,21,29,[45][46][47][48][49], including our present one.…”

Section: Discussionmentioning

confidence: 99%

Enhanced identification of synergistic and antagonistic emergent interactions among three or more drugs

Tekin

Beppler

White

et al. 2016

J. R. Soc. Interface.

100

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Interactions among drugs play a critical role in the killing efficacy of multidrug treatments. Recent advances in theory and experiment for three-drug interactions enable the search for emergent interactions-ones not predictable from pairwise interactions. Previous work has shown it is easier to detect synergies and antagonisms among pairwise interactions when a rescaling method is applied to the interaction metric. However, no study has carefully examined whether new types of normalization might be needed for emergence. Here, we propose several rescaling methods for enhancing the classification of the higher order drug interactions based on our conceptual framework. To choose the rescaling that best separates synergism, antagonism and additivity, we conducted bacterial growth experiments in the presence of single, pairwise and triple-drug combinations among 14 antibiotics. We found one of our rescaling methods is far better at distinguishing synergistic and antagonistic emergent interactions than any of the other methods. Using our new method, we find around 50% of emergent interactions are additive, much less than previous reports of greater than 90% additivity. We conclude that higher order emergent interactions are much more common than previously believed, and we argue these findings for drugs suggest that appropriate rescaling is crucial to infer higher order interactions.

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Section: Discussionmentioning

confidence: 99%

Enhanced identification of synergistic and antagonistic emergent interactions among three or more drugs

Tekin

Beppler

White

et al. 2016

J. R. Soc. Interface.

100

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“…qRT-PCR analysis was carried out as described previously (27). The LY96 mRNA induction was quantified using the QuantiGene 2.0 system (Affymetrix).…”

Section: Gene Expressionmentioning

confidence: 99%

Pharmacological Inhibition of the Histone Lysine Demethylase KDM1A Suppresses the Growth of Multiple Acute Myeloid Leukemia Subtypes

et al. 2016

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Lysine-specific demethylase 1 (KDM1A) is a transcriptional coregulator that can function in both the activation and repression of gene expression, depending upon context. KDM1A plays an important role in hematopoiesis and was identified as a dependency factor in leukemia stem cell populations. Therefore, we investigated the consequences of inhibiting KDM1A in a panel of cell lines representing all acute myelogenous leukemia (AML) subtypes using selective, reversible and irreversible KDM1A smallmolecule inhibitors. Cell models of AML, CML, and T-ALL were potently affected by KDM1A inhibition, and cells bearing RUNX1-RUNX1T1 (AML1-ETO) translocations were especially among the most sensitive. RNAi-mediated silencing of KDM1A also effectively suppressed growth of RUNX1-RUNX1T1-containing cell lines. Furthermore, pharmacologic inhibition of KDM1A resulted in complete abrogation of tumor growth in an AML xenograft model harboring RUNX1-RUNX1T1 translocations. We unexpectedly found that KDM1A-targeting compounds not only inhibited the catalytic activity of the enzyme, but evicted KDM1A from target genes. Accordingly, compound-mediated KDM1A eviction was associated with elevated levels of local histone H3 lysine 4 dimethylation, and increased target gene expression, which was further accompanied by cellular differentiation and induction of cell death. Finally, our finding that KDM1A inhibitors effectively synergize with multiple conventional as well as candidate anti-AML agents affords a framework for potential future clinical application. Cancer Res; 76(7); 1975-88. Ó2016 AACR.

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“…First molecules that directly target EZH2 and compete with the cofactor S-adenosylmethionin (SAM) binding have been described. The inhibitor E7438 has shown efficacy in SMARCB1-mutant Rhabdoid tumors (16) and as well as GSK126 and other reported EZH2 inhibitors (17,18), in EZH2-mutant non-Hodgkin lymphoma (19) where activating mutations are described (20). In addition, effects of EZH2 inhibitors in melanoma (21) (26).…”

Section: Introductionmentioning

confidence: 99%

EZH2 Inhibition Blocks Multiple Myeloma Cell Growth through Upregulation of Epithelial Tumor Suppressor Genes

Hernando

Gelato

Lesche

et al. 2016

Molecular Cancer Therapeutics

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Multiple myeloma is a plasma cell malignancy characterized by marked heterogeneous genomic instability including frequent genetic alterations in epigenetic enzymes. In particular, the histone methyltransferase Enhancer of Zeste Homolog 2 (EZH2) is overexpressed in multiple myeloma. EZH2 is the catalytic component of the polycomb repressive complex 2 (PRC2), a master transcriptional regulator of differentiation. EZH2 catalyzes methylation of lysine 27 on histone H3 and its deregulation in cancer has been reported to contribute to silencing of tumor suppressor genes, resulting in a more undifferentiated state, and thereby contributing to the multiple myeloma phenotype. In this study, we propose the use of EZH2 inhibitors as a new therapeutic approach for the treatment of multiple myeloma. We demonstrate that EZH2 inhibition causes a global reduction of H3K27me3 in multiple myeloma cells, promoting reexpression of EZH2-repressed tumor suppressor genes in a subset of cell lines. As a result of this transcriptional activation, multiple myeloma cells treated with EZH2 inhibitors become more adherent and less proliferative compared with untreated cells. The antitumor efficacy of EZH2 inhibitors is also confirmed in vivo in a multiple myeloma xenograft model in mice. Together, our data suggest that EZH2 inhibition may provide a new therapy for multiple myeloma treatment and a promising addition to current treatment options. Mol Cancer Ther; 15(2); 287-98. Ó2015 AACR.

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EZH2 Inhibitor Efficacy in Non-Hodgkin’s Lymphoma Does Not Require Suppression of H3K27 Monomethylation

Cited by 132 publications

References 48 publications

Enhanced identification of synergistic and antagonistic emergent interactions among three or more drugs

Enhanced identification of synergistic and antagonistic emergent interactions among three or more drugs

Pharmacological Inhibition of the Histone Lysine Demethylase KDM1A Suppresses the Growth of Multiple Acute Myeloid Leukemia Subtypes

EZH2 Inhibition Blocks Multiple Myeloma Cell Growth through Upregulation of Epithelial Tumor Suppressor Genes

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