> Details

Brach, Dorothy; Johnston-Blackwell, Danielle; Drew, Allison; Lingaraj, Trupti; Motwani, Vinny; Warholic, Natalie M.; Feldman, Igor; Plescia, Christopher; Smith, Jesse J.; Copeland, Robert A.; Keilhack, Heike; Chan-Penebre, Elayne; Knutson, Sarah K.; Ribich, Scott A.; Raimondi, Alejandra; Thomenius, Michael J.

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

Reference
management

Bookmarks

Remove from
bookmarks

Share this on Whatsapp

Close

Bookmarks



You can manage bookmarks using lists, please log in to your user account for this.
  • Media type: E-Article
  • Title: EZH2 Inhibition by Tazemetostat Results in Altered Dependency on B-cell Activation Signaling in DLBCL
  • Contributor: Brach, Dorothy; Johnston-Blackwell, Danielle; Drew, Allison; Lingaraj, Trupti; Motwani, Vinny; Warholic, Natalie M.; Feldman, Igor; Plescia, Christopher; Smith, Jesse J.; Copeland, Robert A.; Keilhack, Heike; Chan-Penebre, Elayne; Knutson, Sarah K.; Ribich, Scott A.; Raimondi, Alejandra; Thomenius, Michael J.
  • Published: American Association for Cancer Research (AACR), 2017
  • Published in: Molecular Cancer Therapeutics, 16 (2017) 11, Seite 2586-2597
  • Language: English
  • DOI: 10.1158/1535-7163.mct-16-0840
  • ISSN: 1535-7163; 1538-8514
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title> <jats:p>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.</jats:p>
  • Access State: Open Access