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

Abstract

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.

Molecular and Genetic Characterization of MHC Deficiency Identifies EZH2 as Therapeutic Target for Enhancing Immune Recognition

“…DLBCL cell lines were exposed at 3 concentrations (in DMSO: 0 μmol/L, 1 μmol/L, 5 μmol/L) of tazemetostat (EPZ-6438) for 7 days and analyzed for cell viability as before. Cells were seeded in triplicate (100,000 cells/ mL) and split every 3 to 4 days as previously described (27,50). After 7 days of treatment, cells were stained using the following fluorescent-labeled anti-human antibodies: FITC-conjugated anti-HLA-ABC, FITC-conjugated anti-human HLA-DR/DP/DQ, mouse IgG1 K isotype control, mouse IgG2a K isotype control (all from BD Biosciences).…”

Targeting EZH2 for the treatment of hepatosplenic T-cell lymphoma

“…EZH2 inhibitors, such as tazemetostat, have been tested in vitro and in mouse models of B-cell lymphoma and are currently in clinical trials with early promising results. [13][14][15][16][17] We thus conducted a mouse preclinical study with tazemetostat. NSG mice were injected with spleen cells from the PDX model and monitored for disease establishment.…”

Epigenetic Regulation of EMT (Epithelial to Mesenchymal Transition) and Tumor Aggressiveness: A View on Paradoxical Roles of KDM6B and EZH2

“…Indeed, EZH2 inhibition led to the activation of B-cell pathway. A better understanding of the EZH2 target genes allowed the authors to associate Tazemetostat with B-cell pathway inhibitors to increase the specificity and the efficacy of this treatment in B-cell lymphoma with wild-type EZH2 [100]. Funding: Camille Lachat was supported by a fellowship from the MESR (Ministère de l'Enseignement Supérieur et de la Recherché).…”