EZH2 inhibition by tazemetostat results in altered dependency on B-cell activation signaling in DLBCL

The EZH2 small molecule inhibitor tazemetostat (EPZ-6438) is currently being evaluated in phase II clinical trials for the treatment of non-Hodgkin's Lymphoma (NHL).  We have previously shown that EZH2 inhibitors display an anti-proliferative effect in multiple pre-clinical 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 co-treatment with tazemetostat and glucocorticoid receptor agonists lead to a synergistic anti-proliferative 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.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2isFMBr