Synergistic Anti-Tumor Activity of EZH2 Inhibitors and Glucocorticoid Receptor Agonists in Models of Germinal Center Non-Hodgkin Lymphomas

Knutson, Sarah K.; Warholic, Natalie M.; Johnston, L. Danielle; Klaus, Christine; Wigle, Tim J.; Iwanowicz, Dorothy; Littlefield, Bruce A.; Porter-Scott, Margaret; Smith, J. Joshua; Moyer, Mikel P.; Copeland, Robert A.; Pollock, Roy M.; Kuntz, Kevin W.; Raimondi, Alejandra; Keilhack, Heike

doi:10.1371/journal.pone.0111840

Cited by 66 publications

(52 citation statements)

References 41 publications

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“…These findings suggest that wild-type EZH2 lymphomas have additional active pathways that support their growth and survival. A previous study has demonstrated a synergistic relationship between tazemetostat and glucocorticoids in both wild-type and mutant EZH2 DLBCL cell lines (26). We present here that in addition to glucocorticoids, agents that selectively target the B-cell receptor pathway, ibrutinib (BTKi) and tamatinib (SYKi) also have a synergistic relationship with tazemetostat.…”

Section: Discussionmentioning

confidence: 56%

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EZH2 Inhibition by Tazemetostat Results in Altered Dependency on B-cell Activation Signaling in DLBCL

Brach

Johnston-Blackwell

Drew

et al. 2017

Molecular Cancer Therapeutics

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The EZH2 small-molecule inhibitor tazemetostat (EPZ-6438) is currently being evaluated in phase II clinical trials for the treatment of non-Hodgkin lymphoma (NHL). We have previously shown that EZH2 inhibitors display an antiproliferative effect in multiple preclinical models of NHL, and that models bearing gain-of-function mutations in EZH2 were consistently more sensitive to EZH2 inhibition than lymphomas with wild-type (WT) EZH2. Here, we demonstrate that cell lines bearing EZH2 mutations show a cytotoxic response, while cell lines with WT-EZH2 show a cytostatic response and only tumor growth inhibition without regression in a xenograft model. Previous work has demonstrated that cotreatment with tazemetostat and glucocorticoid receptor agonists lead to a synergistic antiproliferative effect in both mutant and wild-type backgrounds, which may provide clues to the mechanism of action of EZH2 inhibition in WT-EZH2 models. Multiple agents that inhibit the B-cell receptor pathway (e.g., ibrutinib) were found to have synergistic benefit when combined with tazemetostat in both mutant and WT-EZH2 backgrounds of diffuse large B-cell lymphomas (DLBCL). The relationship between B-cell activation and EZH2 inhibition is consistent with the proposed role of EZH2 in B-cell maturation. To further support this, we observe that cell lines treated with tazemetostat show an increase in the B-cell maturation regulator, PRDM1/BLIMP1, and gene signatures corresponding to more advanced stages of maturation. These findings suggest that EZH2 inhibition in both mutant and wild-type backgrounds leads to increased Bcell maturation and a greater dependence on B-cell activation signaling.

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Section: Discussionmentioning

confidence: 56%

“…Tazemetostat was previously shown to have a synergistic relationship with glucocorticoid receptor agonists (GRAG) in cotreatment models of DLBCL (26). This work showed that cell lines with wild-type EZH2 were sensitive to the tazemetostat/GRAG combination, while only showing modest effects with single-agent tazemetostat.…”

Section: Introductionmentioning

confidence: 91%

EZH2 Inhibition by Tazemetostat Results in Altered Dependency on B-cell Activation Signaling in DLBCL

Brach

Johnston-Blackwell

Drew

et al. 2017

Molecular Cancer Therapeutics

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“…4A, B) are strikingly different from those reported by Cao et al, in which omission of WDR5 has essentially no effect on the SET1A activity, while the MLL1 activity is nearly completely eliminated. 43 With regard to the points just discussed, it is worth noting the recent spate of successes in developing potent, SETtargeted, SAM-competitive inhibitors of EZH2 [56][57][58][59][60][61][62] and to also note that the MLL/SET1 family presents a number of features that parallel those of the EZHs. First, despite one group's catalysis of a gene repressive modification (EZH, H3K27 methylation) and the others catalysis of an activating one (MLL/ SET1, H3K4 methylation), the two groups share the same branch of the KMT phylogeny tree.…”

Section: Discussionmentioning

confidence: 99%

Development and Use of Assay Conditions Suited to Screening for and Profiling of SET-Domain-Targeted Inhibitors of the MLL/SET1 Family of Lysine Methyltransferases

Ferry

Smith

Denney

et al. 2015

ASSAY and Drug Development Technologies

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Methylation of histone H3 lysine-4 (H3K4) is an important, regulatory, epigenetic post-translational modification associated with actively transcribed genes. In humans, the principal mediators of this modification are part of the MLL/SET1 family of methyltransferases, which comprises six members, MLLs1-4 and SET1A/SET1B. Aberrations in the structure, expression, and regulation of these enzymes are implicated in various disease states, making them important potential targets for drug discovery, particularly for oncology indications. The MLL/SET1 family members are most enzymatically active when part of a ''core complex,'' the catalytic SET-domain-containing subunits bound to a subcomplex consisting of the proteins WDR5, RbBP5, Ash2L and a homodimer of DPY-30 (WRAD 2 ). The necessity of MLL/SET1 members to bind WRAD 2 for full activity is the basis of a particular drug development strategy, which seeks to disrupt the interaction between the MLL/SET1 subunits and WDR5. This strategy is not without its theoretical and practical drawbacks, some of which relate to the ease with which complexes of Escherichia coli-expressed MLL/SET1 and WRAD 2 fall apart. As an alternative strategy, we explore ways to stabilize the complex, focusing on the use of an excess of WRAD 2 to drive the binding equilibria toward complex formation while maintaining low concentrations of the catalytic subunits. The purpose of this approach is to seek inhibitors that bind the SET domain, an approach proven successful with the related, but inherently more stable, enhancer of zeste homolog 2 (EZH2) complex.

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“…Although it is an analogue of GSK126, it is less selective for EZH1 [105,109] . Remarkably, EPZ-6438 is recently going through clinical testing for Non-Hodgkin Lymphomas patients [110] .…”

Section: Sam Analoguesmentioning

confidence: 99%

“…Standard Non-Hodgkin Lymphoma therapy is a combination of several drugs, called CHOP (Cyclophosphamide, Hydroxyldaunorubicin, Oncovin, and Prednisone). Studies in vitro and in vivo demonstrated that the combination of EPZ-6438 with CHOP increases anti-proliferative benefits compared to treatment with the EZH2 inhibitor alone, and this effect is thought to be mediated by glucocorticoid receptor agonists such as Prednisolone, the active metabolite of Prednisone [110] . Moreover, other studies investigated the inhibition of EZH2 in combination with conventional therapies in prostate cancer.…”

Section: Combination Of Ezh2 Inhibitor With Other Drugsmentioning

confidence: 99%

Targeting Enhancer of Zeste Homolog 2 as a promising strategy for cancer treatment

Marchesi

Bagella

2016

WJCO

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Polycomb group proteins represent a global silencing system involved in development regulation. In specific, they regulate the transition from proliferation to differentiation, contributing to stem-cell maintenance and inhibiting an inappropriate activation of differentiation programs. Enhancer of Zeste Homolog 2 (EZH2) is the catalytic subunit of Polycomb repressive complex 2, which induces transcriptional inhibition through the tri-methylation of histone H3, an epigenetic change associated with gene silencing. EZH2 expression is high in precursor cells while its level decreases in differentiated cells. EZH2 is upregulated in various cancers with high levels associated with metastatic cancer and poor prognosis. Indeed, aberrant expression of EZH2 causes the inhibition of several tumor suppressors and differentiation genes, resulting in an uncontrolled proliferation and tumor formation. This editorial explores the role of Polycomb repressive complex 2 in cancer, focusing in particular on EZH2. The canonical function of EZH2 in gene silencing, the non-canonical activities as the methylation of other proteins and the role in gene transcriptional activation, were summarized. Moreover, mutations of EZH2, responsible for an increased methyltransferase activity in cancer, were recapitulated. Finally, various drugs able to inhibit EZH2 with different mechanism were described, specifically underscoring the effects in several cancers, in order to clarify the role of EZH2 and understand if EZH2 blockade could be a new strategy for developing specific therapies or a way to increase sensitivity of cancer cells to standard therapies.

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Synergistic Anti-Tumor Activity of EZH2 Inhibitors and Glucocorticoid Receptor Agonists in Models of Germinal Center Non-Hodgkin Lymphomas

Cited by 66 publications

References 41 publications

EZH2 Inhibition by Tazemetostat Results in Altered Dependency on B-cell Activation Signaling in DLBCL

EZH2 Inhibition by Tazemetostat Results in Altered Dependency on B-cell Activation Signaling in DLBCL

Development and Use of Assay Conditions Suited to Screening for and Profiling of SET-Domain-Targeted Inhibitors of the MLL/SET1 Family of Lysine Methyltransferases

Targeting Enhancer of Zeste Homolog 2 as a promising strategy for cancer treatment

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