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

• Type of Material: Article
• Authors: Hanna Scholze, Weill Cornell Medical College; Regan E. Stephenson, Cornell University; Raymond Reynolds, Weill Cornell Medical College; Shivem Shah, Cornell University; Rishi Puri, Cornell University; Scott D. Butler, Cornell University; Vicenta Trujillo-Alonso, Weill Cornell Medical College; Matthew R. Teater, Weill Cornell Medical College; Herman van Besien, Weill Cornell Medical College; Destini Gibbs-Curtis, Weill Cornell Medical College; Hideki Ueno, Icahn School of Medicine at Mount Sinai; Salma Parvin, Dana Farber Cancer Institute; Anthony Letai, Dana Farber Cancer Institute; Susan Mathew, Weill Cornell Medical College; Ankur Singh, Georgia Institute of Technology; Ethel Cesarman, Weill Cornell Medical College; Ari Melnick, Weill Cornell Medical College; Lisa Giulino-Roth, Weill Cornell Medical College
• Language: English
• Date: 2020-10-27
• Publisher: AMER SOC HEMATOLOGY
• Publication Version: Final Published Version
• Copyright Statement: © 2020 by The American Society of Hematology
• Final Published Version (URL): http://dx.doi.org/10.1182/bloodadvances.2020002580
• Title of Journal or Parent Work: BLOOD ADVANCES
• Volume: 4
• Issue: 20
• Start Page: 5226
• End Page: 5231
• Grant/Funding Information: This work was supported by National Institutes of Health, National Cancer Institute grant K08 CA219471 (L.G.-R.), The Leukemia & Lymphoma Society Specialized Center of Research Program (L.G.-R., A.M., and E.C.), National Institutes of Health, National Cancer Institute (grant 1R01 CA238745-01A1) (A.S.), The Innovative Molecular Analysis Technology program of the National Institutes of Health, National Cancer Institute (grant 5R33CA212968-03) (A.S.), a National Science Foundation CAREER award (DMR-1554275) (A.S.), and a US Department of Defense Congressionally Directed Medical Research Program Cancer Career Development Award (W81XWH-17-1-0215) (A.S.). R.E.S. was the recipient of a National Science Foundation Graduate Research Fellowship (DGE-1650441).
• Keywords: Hematology; VENETOCLAX; MUTATIONS; Life Sciences & Biomedicine; Science & Technology; LYMPHOMA
• Research Categories: Health Sciences, Oncology; Health Sciences, Medicine and Surgery

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.