Artikel ; Online: Combined EZH2 and Bcl-2 inhibitors as precision therapy for genetically defined DLBCL subtypes.
2020 Band 4, Heft 20, Seite(n) 5226–5231
Abstract: Molecular alterations in the histone methyltransferase EZH2 and the antiapoptotic protein Bcl-2 frequently co-occur in diffuse large B-cell lymphoma (DLBCL). Because DLBCL tumors with these characteristics are likely dependent on both oncogenes, dual ... ...
| Abstract | Molecular alterations in the histone methyltransferase EZH2 and the antiapoptotic protein Bcl-2 frequently co-occur in diffuse large B-cell lymphoma (DLBCL). Because DLBCL tumors with these characteristics are likely dependent on both oncogenes, dual targeting of EZH2 and Bcl-2 is a rational therapeutic approach. We hypothesized that EZH2 and Bcl-2 inhibition would be synergistic in DLBCL. To test this, we evaluated the EZH2 inhibitor tazemetostat and the Bcl-2 inhibitor venetoclax in DLBCL cells, 3-dimensional lymphoma organoids, and patient-derived xenografts (PDXs). We found that tazemetostat and venetoclax are synergistic in DLBCL cells and 3-dimensional lymphoma organoids that harbor an EZH2 mutation and an IGH/BCL2 translocation but not in wild-type cells. Tazemetostat treatment results in upregulation of proapoptotic Bcl-2 family members and priming of mitochondria to BH3-mediated apoptosis, which may sensitize cells to venetoclax. The combination of tazemetostat and venetoclax was also synergistic in vivo. In DLBCL PDXs, short-course combination therapy resulted in complete remissions that were durable over time and associated with superior overall survival compared with either drug alone. |
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| Mesh-Begriff(e) | Antineoplastic Agents/therapeutic use ; Apoptosis ; Bridged Bicyclo Compounds, Heterocyclic/pharmacology ; Enhancer of Zeste Homolog 2 Protein/antagonists & inhibitors ; Humans ; Lymphoma, Large B-Cell, Diffuse/drug therapy ; Lymphoma, Large B-Cell, Diffuse/genetics ; Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors ; Sulfonamides/pharmacology | |||||
| Chemische Substanzen | Antineoplastic Agents ; BCL2 protein, human ; Bridged Bicyclo Compounds, Heterocyclic ; Proto-Oncogene Proteins c-bcl-2 ; Sulfonamides ; EZH2 protein, human (EC 2.1.1.43) ; Enhancer of Zeste Homolog 2 Protein (EC 2.1.1.43) | |||||
| Sprache | Englisch | |||||
| Erscheinungsdatum | 2020-10-27 | |||||
| Erscheinungsland | United States | |||||
| Dokumenttyp | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. | |||||
| ZDB-ID | 2915908-8 | |||||
| ISSN | 2473-9537 ; 2473-9529 | |||||
| ISSN (online) | 2473-9537 | |||||
| ISSN | 2473-9529 | |||||
| DOI | 10.1182/bloodadvances.2020002580 | |||||
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| Datenquelle | MEDical Literature Analysis and Retrieval System OnLINE |
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