EZH2 inhibitor SHR2554 enhances the anti-tumor efficacy of HDAC inhibitor Chidamide through STAT1 in T-cell lymphoma.

T-cell lymphoma (TCL) is a rare subtype of non-Hodgkin lymphoma (NHL) that is associated with a poor prognosis. Although HDAC inhibitors have been approved for TCL treatment for several years, their expected therapeutic efficacy remains unmet in some patients. In this study, we discovered that TCL tumor cells develop resistance to HDAC inhibitor treatment by upregulating the methylation of lysine 27 on histone H3 (H3K27me3) levels. Furthermore, we confirmed the pharmacological efficacy of the EZH2 inhibitor SHR2554 and demonstrated a synergistic effect when combined with the HDAC inhibitor Chidamide through commercial TCL cell lines, in vivo cell-derived xenograft, and patient-derived xenograft cancer models. We inferred that STAT1 was the key driver of the synergistic effect using RNA-seq and ChIP-seq analysis. Our findings provide sufficient preclinical evidence in support of a potential combination therapy strategy for TCL patients.