Title | Combined EZH2 and Bcl-2 inhibitors as precision therapy for genetically defined DLBCL subtypes. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | Scholze H, Stephenson RE, Reynolds R, Shah S, Puri R, Butler SD, Trujillo-Alonso V, Teater MR, van Besien H, Gibbs-Curtis D, Ueno H, Parvin S, Letai A, Mathew S, Singh A, Cesarman E, Melnick A, Giulino-Roth L |
Journal | Blood Adv |
Volume | 4 |
Issue | 20 |
Pagination | 5226-5231 |
Date Published | 2020 10 27 |
ISSN | 2473-9537 |
Keywords | Antineoplastic Agents, Apoptosis, Bridged Bicyclo Compounds, Heterocyclic, Enhancer of Zeste Homolog 2 Protein, Humans, Lymphoma, Large B-Cell, Diffuse, Proto-Oncogene Proteins c-bcl-2, Sulfonamides |
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. |
DOI | 10.1182/bloodadvances.2020002580 |
Alternate Journal | Blood Adv |
PubMed ID | 33104794 |
PubMed Central ID | PMC7594393 |
Grant List | R01 CA238745 / CA / NCI NIH HHS / United States R33 CA212968 / CA / NCI NIH HHS / United States R35 CA242427 / CA / NCI NIH HHS / United States |
Related Faculty:
Ethel Cesarman, M.D., Ph.D.