The Synergistic Anti-Tumor Activity of EZH2 Inhibitor SHR2554 and HDAC Inhibitor Chidamide through ORC1 Reduction of DNA Replication Process in Diffuse Large B Cell Lymphoma

Abstract

Background: Upregulation of H3K27me3 induced by EZH2 overexpression or somatic heterozygous mutations were implicated in lymphomagenesis. It has been demonstrated that several EZH2-target agents have notable therapeutic effects in EZH2-mutant B-cell lymphoma patients. Here we present a novel highly selective EZH2 inhibitor SHR2554 and possible combination strategy in diffuse large B-cell lymphoma (DLBCL). Methods: Cell proliferation, cell cycle and apoptosis were analyzed by CellTiter-Glo Luminescent Cell Viability Assay and flow cytometry. Western Blot was used to detect the expression of related proteins. The gene expression profiling post combination treatment was analyzed by RNA-Seq. Finally, CDX and PDX models were used to evaluate the synergistic anti-tumor effects of the combination treatment in vivo. Results: The novel EZH2 inhibitor SHR2554 inhibited proliferation and induced G1 phase arrest in EZH2-mutant DLBCL cell lines. The combination of EZH2 inhibitor SHR2554 with histone deacetylase (HDAC) inhibitor chidamide (hereafter referred to as HBI8000) exerted synergistic anti-proliferative activity in vitro and in vivo. Gene expression profile analysis revealed dramatic inhibition of the DNA replication process in combined treatment. Conclusions: SHR2554, a potent, highly selective small molecule inhibitor of EZH2, inhibited EZH2-mutant DLBCL more significantly in vitro and in vivo. The combination of HDAC inhibitor HBI8000 with EZH2 inhibitor SHR2554 exhibited dramatic anti-tumor activity in both mutant and wild-type DLBCL, which may become a potential therapeutic modality for the treatment of DLBCL patients.

Targeting Triple-Negative Breast Cancer by a Novel Proteolysis Targeting Chimera Degrader of Enhancer of Zeste Homolog 2

“…15 When phosphorylated at Thr367 by p38, EZH2 can dissociate from PRC2, enter the cytoplasm, and drive migration and invasion of metastasis in PR-, ER-, and triplenegative breast cancers in a PRC2-independent manner. 22 Several EZH2 catalytic inhibitors, such as GSK126, 9 CPI-1205, 23 PF-06821497, 24 SHR2554, 25 DS-3201, 26 EPZ-6438 27,28 (also known as Tazemetostat), UNC1999, 29 and C24, 30 have been developed. Six of them (CPI-1205, GSK126, EPZ-6438, SHR2554, DS-3201, and PF-06821497) have advanced into clinical trials for investigating their effects in a variety of H3K27me3-dependent tumors, such as DLBCL 5,31,32 (Figure 1).…”

“…Several EZH2 catalytic inhibitors, such as GSK126, CPI-1205, PF-06821497, SHR2554, DS-3201, EPZ-6438 , (also known as Tazemetostat), UNC1999, and C24, have been developed. Six of them (CPI-1205, GSK126, EPZ-6438, SHR2554, DS-3201, and PF-06821497) have advanced into clinical trials for investigating their effects in a variety of H3K27me3-dependent tumors, such as DLBCL ,, (Figure ).…”

Preclinical Evaluation of the HDAC Inhibitor Chidamide in Transformed Follicular Lymphoma

“…As the activity of chidamide, as monotherapy at the doses tested in this study was modest, understanding potential biomarkers that are predictive of response is very important for the design of future clinical trials (51). In addition, emerging data from in vitro studies indicate that HDAC inhibitors, such as chidamide, may have improved activity when used in combination therapy (52)(53)(54). To this end, several recent studies have provided a strong preclinical rationale for combination with chemotherapy, immunotherapy, or molecular targeted therapy, paving the way for possible studies in selected populations (53)(54)(55).…”

“…In addition, emerging data from in vitro studies indicate that HDAC inhibitors, such as chidamide, may have improved activity when used in combination therapy (52)(53)(54). To this end, several recent studies have provided a strong preclinical rationale for combination with chemotherapy, immunotherapy, or molecular targeted therapy, paving the way for possible studies in selected populations (53)(54)(55). In our previous work, we revealed that ABT-199 (25) or MLL-menin inhibitor (56) has a synergistic inhibitory effect on acute myeloid leukemia cells when combined with chidamide.…”

“…In our previous work, we revealed that ABT-199 ( 25 ) or MLL-menin inhibitor ( 56 ) has a synergistic inhibitory effect on acute myeloid leukemia cells when combined with chidamide. Combination with a demethylating agent also showed benefit in diffuse large B cell lymphomas (DLBCLs) ( 53 ). In addition, chidamide could increase PD-L1 expression in the tumor microenvironment, and preclinical studies have demonstrated synergy between chidamide, and PD-1 blockade in solid tumors ( 55 , 57 ).…”