Combined EZH2 and Bcl-2 inhibitors as precision therapy for genetically defined DLBCL subtypes.

TitleCombined EZH2 and Bcl-2 inhibitors as precision therapy for genetically defined DLBCL subtypes.
Publication TypeJournal Article
Year of Publication2020
AuthorsScholze 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
JournalBlood Adv
Date Published2020 10 27
KeywordsAntineoplastic 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

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.

Alternate JournalBlood Adv
PubMed ID33104794
PubMed Central IDPMC7594393
Grant ListR01 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.

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