Abstract C017: Preclinical evaluation of EZH2 inhibitor tazemetostat-based combination therapies to treat lymphoma and solid tumors

Abstract Background: The histone methyltransferase EZH2, often harboring gain-of function mutations in B-cell lymphoma and commonly overexpressed in solid tumors, promotes tumor progression by H3K27me3-mediated epigenetic gene silencing. Tazemetostat (TAZ), a selective EZH2 inhibitor, was approved by FDA for epithelioid sarcoma and follicular lymphoma. Given the ubiquitous nature of epigenetic regulation, TAZ is currently being developed for additional indications and combination approaches. This study evaluated novel combinations of TAZ with two different agents: the PI3Kδ inhibitor amdizalisib (HMPL-689) in lymphoma, and surufatinib (HMPL-012), a VEGFR, FGFR1, and CSF-1R inhibitor that modulates tumor vasculature and immune microenvironment in solid tumors. Methods: Cell viability was investigated in a panel of tumor cell lines using CellTiter-Glo luminescent assays. Cell apoptosis was quantified by flow cytometry using APC Annexin V Apoptosis Detection Kit. In vivo efficacy was evaluated in multiple human tumor cell line-derived subcutaneous xenograft models. RNA-seq was conducted to identify gene expression patterns. Results: In multiple human B-cell lymphoma cell lines with wild-type or mutant EZH2, the combination of TAZ and amdizalisib exhibited stronger inhibitory effect on cell viability than either agent alone. Similarly enhanced inhibition of cell viability with combination treatment was also observed in T-cell lymphoma cell lines. Flow cytometric analysis confirmed increased apoptosis in the combination treatment across multiple lymphoma cell lines. In human B-cell lymphoma SU-DHL-6 xenograft model, twice daily oral administration of TAZ with amdizalisib induced statistically significant higher tumor growth inhibition (TGI) of 87.3% compared to monotherapies (TAZ: -7.6%, amdizalisib: 60.9%). TAZ in combination with surufatinib was evaluated in multiple human tumor cell line-derived subcutaneous xenograft models, including SCLC, NSCLC, ovarian and prostate cancer. In SCLC NCI-H69 model, oral administration of TAZ plus surufatinib yielded 102.8% TGI versus either monotherapy (TAZ: 21.3%, surufatinib: 37.0%), most of the mice that received combination treatment displayed tumor regression. RNA-seq analysis identified significant down-regulation of cell cycle and MYC-pathway genes following the combination treatment. In another SCLC tumor model DMS-114, combination also demonstrated improved anti-tumor efficacy, along with enhanced anti-angiogenic effect compared with surufatinib. Conclusion: Tazemetostat showed synergistic anti-tumor effects and increased apoptosis induction with PI3Kδ inhibitor amdizalisib in B and T-cell lymphomas. Its combination with surufatinib induced cell cycle arrest, suppressed oncogenic MYC pathway and enhanced anti-angiogenesis, consequently resulted in improved anti-tumor efficacy in solid tumors. Citation Format: Huijing Yu, Jia Hu, Shiming Fan, Juntao Yu, Qi Ding, Ying Yu, Tingwen Li, Xiaoya Wang, Longxian Jiao, Dongxia Shi, Min Cheng, Linfang Wang, Yongxin Ren, Weiguo Su. Preclinical evaluation of EZH2 inhibitor tazemetostat-based combination therapies to treat lymphoma and solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C017.