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EZH2 Inhibition by Tazemetostat Results in Altered Dependency on B-cell Activation Signaling in DLBCL
Dorothy Brach1, Danielle Johnston-Blackwell1, Allison Drew1
1Epizyme Inc., Cambridge, Massachusetts.
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.
Insights
Tazemetostat, an EZH2 inhibitor, shows cytotoxic effects in EZH2-mutated non-Hodgkin lymphoma models. It induces B-cell maturation and enhances sensitivity to B-cell receptor pathway inhibitors in both mutant and wild-type EZH2 lymphomas.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- EZH2 inhibitors like tazemetostat show antiproliferative effects in non-Hodgkin lymphoma (NHL) models.
- Models with gain-of-function mutations in EZH2 are more sensitive to EZH2 inhibition than those with wild-type (WT) EZH2.
- The mechanism of EZH2 inhibition in WT-EZH2 models requires further elucidation.
Purpose of the Study:
- To investigate the differential response of EZH2-mutant versus WT-EZH2 lymphoma models to tazemetostat.
- To explore synergistic effects of tazemetostat in combination with other agents.
- To elucidate the mechanism of EZH2 inhibition in WT-EZH2 lymphoma models.
Main Methods:
- Treatment of NHL cell lines and xenograft models with tazemetostat.
- Assessment of cytotoxic versus cytostatic responses based on EZH2 mutation status.
- Combination studies with glucocorticoid receptor agonists and B-cell receptor pathway inhibitors (e.g., ibrutinib).
- Analysis of B-cell maturation markers, including PRDM1/BLIMP1, and gene expression signatures.
Main Results:
- EZH2-mutant cell lines exhibited a cytotoxic response to tazemetostat, while WT-EZH2 cell lines showed a cytostatic response with tumor growth inhibition but no regression.
- Synergistic antiproliferative effects were observed when combining tazemetostat with glucocorticoid receptor agonists in both mutant and WT-EZH2 backgrounds.
- Combinations of tazemetostat with B-cell receptor pathway inhibitors demonstrated synergistic benefits in diffuse large B-cell lymphoma (DLBCL) models with both mutant and WT-EZH2.
- Tazemetostat treatment led to increased PRDM1/BLIMP1 expression and gene signatures associated with advanced B-cell maturation.
Conclusions:
- EZH2 inhibition induces a cytotoxic response in EZH2-mutant NHL and a cytostatic response in WT-EZH2 NHL.
- EZH2 inhibition promotes B-cell maturation, increasing dependence on B-cell activation signaling.
- Combination therapies involving tazemetostat hold promise for treating both EZH2-mutant and WT-EZH2 lymphomas, particularly in DLBCL.
