Abstract B029: Combinations of metformin and BH3-mimetic drugs synergistically induce immunogenic cell death in breast cancer cells

Abstract

Abstract There is a compelling medical need for novel and safe treatment options for patients with advanced and difficult to treat breast cancer. Our previous findings have demonstrated that a combination of metformin and navitoclax (BCL-2/BCL-XL inhibitor) successfully prevents tumor growth in patient derived xenograft and syngrafted mouse models of aggressive MYC-driven breast cancer. This outcome is due to the synthetic lethal action of these drugs in tumors with elevated MYC expression. Here, we explored the combinations of metformin with all clinically applicable anti-apoptotic BCL-2 family protein inhibitors (BH3-mimetics) in a panel of 15 triple-negative breast cancer cell lines with distinct endogenous MYC levels, as well as inducible MYC models. We used cytotoxicity assays and analyzed the data with SynergyFinder, an interactive analysis and visualization tool, to calculate the degree of combination synergy utilizing Zero interaction potency reference model. Through these cytotoxicity assays, we defined which metformin and BH3-mimetic drug combination induces most synergistic cell death in a MYC-synthetic lethal manner. Additionally, we used DAMP reporter cell lines and peripheral blood mononuclear cell-based dendritic cell activation assays to evaluate the immunogenic potential of combination-induced cell death. We show that targeting MCL-1 or BCL-2/XL with BH3-mimetics MIK-665 and navitoclax, respectively, and combining them with metformin, induces synergistic cell death in MYC-high cancer cells. We also show that cell death caused by these drug combinations promotes maturation of dendritic cells. In conclusion, targeting MYC-high tumors with synthetic lethal strategies, including BH3-mimetics and metformin, may offer new opportunities to combine with immunotherapies for the treatment of breast cancer. Citation Format: Mariel Savelius, Linda Id, Johanna Anttila, Ruixian Liu, Ilida Suleymanova, Jani Saarela, Juha Klefström. Combinations of metformin and BH3-mimetic drugs synergistically induce immunogenic cell death in breast cancer cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B029.