Combined EZH2 and Bcl-2 inhibitors as precision therapy for genetically defined DLBCL subtypes
Hanna Scholze, Regan E. Stephenson, Raymond Reynolds, Shivem B. Shah, Rishi Puri, Scott D. Butler, Vicenta Trujillo-Alonso, Matthew Teater, Herman van Besien, Destini Gibbs-Curtis, Hideki Ueno, Salma Parvin, Anthony Letai, Susan Mathew, Ankur Singh, Ethel Cesarman, Ari Melnick, Lisa Giulino‐Roth
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.