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

Autor:	Brach D; Epizyme Inc., Cambridge, Massachusetts., Johnston-Blackwell D; Epizyme Inc., Cambridge, Massachusetts., Drew A; Epizyme Inc., Cambridge, Massachusetts., Lingaraj T; Epizyme Inc., Cambridge, Massachusetts., Motwani V; Epizyme Inc., Cambridge, Massachusetts., Warholic NM; Epizyme Inc., Cambridge, Massachusetts., Feldman I; Epizyme Inc., Cambridge, Massachusetts., Plescia C; Epizyme Inc., Cambridge, Massachusetts., Smith JJ; Epizyme Inc., Cambridge, Massachusetts., Copeland RA; Epizyme Inc., Cambridge, Massachusetts., Keilhack H; Epizyme Inc., Cambridge, Massachusetts., Chan-Penebre E; Epizyme Inc., Cambridge, Massachusetts., Knutson SK; Epizyme Inc., Cambridge, Massachusetts., Ribich SA; Epizyme Inc., Cambridge, Massachusetts., Raimondi A; Epizyme Inc., Cambridge, Massachusetts. araimondi@epizyme.com mthomenius@epizyme.com., Thomenius MJ; Epizyme Inc., Cambridge, Massachusetts. araimondi@epizyme.com mthomenius@epizyme.com.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2017 Nov; Vol. 16 (11), pp. 2586-2597. Date of Electronic Publication: 2017 Aug 23.
DOI:	10.1158/1535-7163.MCT-16-0840
Abstrakt:	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.)
Databáze:	MEDLINE
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