Dual Targeting of EZH2 Degradation and EGFR/HER2 Inhibition for Enhanced Efficacy against Burkitt’s Lymphoma

SIMPLE SUMMARY: Burkitt’s lymphoma (BL) is an aggressive type of non-Hodgkin lymphoma that originates from B-cells. It is characterized by translocation of the MYC gene, leading to the upregulation of this gene and subsequently causing overexpression of EZH2. Since BL shows rapid involvement, the development of a new effective agent is needed. In this study, we targeted EZH2 and HER2/neu-EGFR, both of which are related to cell proliferation and overexpression-induced tumors. We conducted a study using a combination of MS1943, EZH2 degrader, lapatinib, and HER2/neu-EGFR inhibitor. We demonstrated that a combination of MS1943 and lapatinib induced apoptosis in Daudi cells with S and G2/M phase arrest in Ramos and Daudi cells. These promising agents could prove to be a new therapeutic option against BL. ABSTRACT: EZH2, a histone methyltransferase, contributes significantly to cancer cell survival and proliferation. Although various EZH2 inhibitors have demonstrated promise in treating lymphoma, they have not fully managed to curb lymphoma cell proliferation despite effective reduction of the H3K27me3 mark. We used MS1943, an EZH2 selective degrader, which successfully diminishes EZH2 levels in lymphoma cells. Additionally, lapatinib, a dual inhibitor of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) tyrosine kinases, targets a receptor protein that regulates cell growth and division. The overexpression of this protein is often observed in lymphoma cells. Our study aims to combine these two therapeutic targets to stimulate apoptosis pathways and potentially suppress Burkitt’s lymphoma cell survival and proliferation in a complementary and synergistic manner. We observed that a combination of MS1943 and lapatinib induced apoptosis in Daudi cells and caused cell cycle arrest at the S and G2/M phases in both Ramos and Daudi cells. This strategy, using a combination of MS1943 and lapatinib, presents a promising therapeutic approach for treating lymphoma and potentially Burkitt’s lymphoma.