P2, N=80, Recruiting, Institute of Hematology & Blood Diseases Hospital, China | Not yet recruiting --> Recruiting

P2, N=10, Active, not recruiting, University of Florida | Trial completion date: Apr 2026 --> Dec 2026

DOX-resistant breast cancer cell models were established and treated with the EZH2 inhibitors tazemetostat or GSK126, alone or in combination with DOX. EZH2 is a critical determinant of DOX resistance in breast cancer by sustaining DNA damage tolerance and metabolic homeostasis. Pharmacological targeting of EZH2 in combination with DOX represents a rational strategy to overcome chemoresistance in breast cancer.

Pharmacological inhibitors of EZH2, including tazemetostat, have shown promise in preclinical melanoma models by restoring antigen presentation, enhancing CD8+ T-cell infiltration, and reversing transcriptional programs associated with immune resistance. This review aims to summarize the role of EZH2 in the molecular pathogenesis of ALM, emphasizing its contributions to epigenetic regulation, tumor plasticity, and immune escape, and discusses emerging therapeutic strategies targeting EZH2-mediated pathways to improve outcomes for this aggressive melanoma subtype.

Notably, TZM monotherapy inhibited tumor growth in both FN- and FP-RMSCRR xenografts, uncovering a therapy-induced vulnerability. Our integrative multi-omics analysis reveals EZH2-dependent molecular programs underpinning radioresistance and supports EZH2 targeting as a rational radiosensitizing and therapeutic strategy in RMS, including recurrent and RT-refractory disease.

P1/2, N=40, Not yet recruiting, Sun Yat-sen University

Valemetostat, which inhibits EZH1/2, as well as tazemetostat in combination with other drugs have been subject of recent research. The purpose of this article is to review the role of EZH2 in normal B cell differentiation and in the pathogenesis of B-Cell lymphomas.

In human aortic endothelial cells exposed to high glucose/tumor necrosis factor-α or serum from patients with coronary artery disease, EZH2 blockade via GSK-126 or short hairpin RNA suppressed EndMT and reversed transcriptional programs assessed by RNA sequencing, including COL4A1 and NR2F2. These findings identify EZH2 as a driver of EndMT in diabetes-associated atherosclerosis and highlight EZH2 inhibition as a potential therapeutic strategy to limit vascular pathology.

P2, N=60, Not yet recruiting, Prostate Cancer Clinical Trials Consortium

We identified a novel ACSS2-H3K9ac-HK2 signaling axis that is characteristically activated in EZH2-non-mutant solid tumors and drives metabolic reprogramming and resistance to EZH2 inhibition.

Notably, we further found that the status of NRF1 expression affected the sensitivity of human cancer cells to EZH2is, including GSK343 and tazemetostat. In conclusion, our findings reveal that NRF1 is a dominant cause of EZH2 overexpression in human cancers and that NRF1 overexpression increases the sensitivity of cancer cells to EZH2is. Active NRF1 and EZH2 expression may be a useful combined predictor for the treatment of cancers with EZH2is.

Functionally, dual pharmacological inhibition of EZH2 (GSK126) and LSD1 (SP2509) suppressed HCC cell proliferation, induced G1-phase arrest, and enhanced apoptosis, as evidenced by increased caspase-3/7 activity and decreased pro-caspase levels. Chromatin immunoprecipitation revealed reduced EZH2, LSD1, and STAT3 occupancy at the GLI1 promoter following dual inhibition, leading to the repression of GLI1 and its downstream targets. Collectively, these findings demonstrate that EZH2 and LSD1 cooperatively sustain GLI1-dependent SHH signaling in HCC, and that dual epigenetic inhibition represents a mechanistically defined therapeutic strategy.