1. EZH2 Inhibition by Tazemetostat Results in Altered Dependency on B-cell Activation Signaling in DLBCL.
- Author
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Brach D, Johnston-Blackwell D, Drew A, Lingaraj T, Motwani V, Warholic NM, Feldman I, Plescia C, Smith JJ, Copeland RA, Keilhack H, Chan-Penebre E, Knutson SK, Ribich SA, Raimondi A, and Thomenius MJ
- Subjects
- Adenine analogs & derivatives, Animals, B-Lymphocytes drug effects, Biphenyl Compounds, Cell Proliferation drug effects, DNA Methylation drug effects, Drug Synergism, Enhancer of Zeste Homolog 2 Protein antagonists & inhibitors, Gene Expression Regulation, Neoplastic drug effects, Humans, Lymphoma, Large B-Cell, Diffuse genetics, Lymphoma, Large B-Cell, Diffuse pathology, Mice, Morpholines, Mutation, Piperidines, Signal Transduction drug effects, Xenograft Model Antitumor Assays, Benzamides administration & dosage, Enhancer of Zeste Homolog 2 Protein genetics, Lymphoma, Large B-Cell, Diffuse drug therapy, Pyrazoles administration & dosage, Pyridones administration & dosage, Pyrimidines administration & dosage
- 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 ., (©2017 American Association for Cancer Research.)
- Published
- 2017
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