EZH2 Inhibition by Tazemetostat Results in Altered Dependency on B-cell Activation Signaling in DLBCL
| Autor: | Sarah K. Knutson, Scott Ribich, Allison Drew, Heike Keilhack, Igor Feldman, J. Joshua Smith, Danielle Johnston-Blackwell, Michael Thomenius, Christopher Plescia, Elayne Chan-Penebre, Trupti Lingaraj, Robert A. Copeland, Vinny Motwani, Alejandra Raimondi, Natalie Warholic, Dorothy Brach |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research Pyridones Morpholines Mutant macromolecular substances Biology medicine.disease_cause Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Piperidines PRDM1 medicine Animals Humans Cytotoxic T cell Enhancer of Zeste Homolog 2 Protein Receptor Cell Proliferation B-Lymphocytes Mutation Adenine Biphenyl Compounds Drug Synergism DNA Methylation medicine.disease Xenograft Model Antitumor Assays Lymphoma Gene Expression Regulation Neoplastic Pyrimidines 030104 developmental biology Oncology chemistry Mechanism of action 030220 oncology & carcinogenesis Ibrutinib Benzamides Immunology Cancer research Pyrazoles Lymphoma Large B-Cell Diffuse medicine.symptom Signal Transduction |
| Zdroj: | Molecular Cancer Therapeutics. 16:2586-2597 |
| ISSN: | 1538-8514 1535-7163 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|