Synergistic Effects of Combined PROTAC-based EZH2 Degrader and METTL3 Inhibitor in Burkitt’s Lymphoma

EZH2 is a methyltransferase that is a critical target for lymphoma treatment.However, it is not yet widely used in clinical settings.PROteolysis TArgeting Chimeras (PROTACs) represent a novel therapeutic strategy aimed at eliminating proteins that have been a challenging target using conventional small molecules.In our previous research, we compared the small molecules-based EZH2 inhibitor used in clinical settings with a PROTAC-based EZH2 degrader.We found that the PROTAC-based degrader was significantly more effective.Building on this, we further investigated the effects of combining the PROTAC-based EZH2 degrader (dEZH2) with a METTL3 inhibitor, both of which have demonstrated effectiveness in inhibiting cell proliferation and inducing apoptosis in Burkitt's lymphoma.Using the CCK-8 assay, we found that both drugs, alone and in combination, significantly inhibited Daudi and Ramos cell growth in a dose-dependent manner.The combined treatment markedly suppressed cell proliferation and induced apoptosis, as confirmed by Annexin V/PI staining.Our results revealed G2/M phase arrest with a significant decrease in the G0/G1 phase by flow cytometry.Our study also showed increased levels of cleaved PARP, cleaved caspase-3, tumor protein p53 (TP53), and PUMA using the western blot technique, indicating enhanced p53-dependent apoptosis.Our findings suggest that the combination therapy of dEZH2 and iMETTL3 could be a promising approach in the treatment of Burkitt's lymphoma.