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 B-cell maturation and a greater dependence on B-cell activation signaling. Mol Cancer Ther; 16(11); 2586-97. ©2017 AACR.
Highlights
Disruption of chromatin modulation is emerging as an important, if not requisite, step in the process of oncogenesis
These findings suggest that mutant EZH2 cell lines have a strong dependency on EZH2 activity for their viability, while very little if any EZH2 activity is required for survival of wildtype EZH2 cell lines
We found that addition of LPS, BAFF, APRIL, or CD40L was able to antagonize the effects of EZH2 inhibition in multiple cell lines (Fig. 2A; Table 1)
Summary
Disruption of chromatin modulation is emerging as an important, if not requisite, step in the process of oncogenesis. Mutations in chromatin modifiers are frequent occurrences in a number of cancers and are often associated with aberrant cell fate decisions [1,2,3]. These lesions are frequent events in non-Hodgkin B-cell Lymphoma. Loss-of-function mutations in EP300, CREBBP, or KMT2D (MLL2) or gain-offunction mutations in EZH2 occur frequently in B-cell lymphomas [4,5,6]. Recent reports have demonstrated that loss of KMT2D or EZH2 gain-of-function leads to disruption of cell fate decisions (e.g., differentiation or apoptosis) and responses to extracellular signaling [7,8,9,10].
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