Abstract 3849: The antidiabetic drug metformin increases pro-apoptotic effect of TRAIL therapy by reducing X-linked inhibitor of apoptosis protein (XIAP) levels in triple-negative breast cancer cells

Most metastatic tumors, such as triple negative breast cancer (TNBC) respond poorly to conventional chemotherapy. We have previously demonstrated that targeting TNF-related apoptosis-inducing ligand receptor-2 (TRAIL-R2) might be an effective pathway against metastatic TNBC. However, many TNBCs are resistant to TRAIL receptor agonists. Here we demonstrate that diabetes drug metformin, previously linked to preventing and treating several types of cancer, enhances sensitivity of TNBC cells to recombinant TRAIL and TRAIL-R2 agonistic humanized monoclonal antibody (lexatumumab)-induced apoptosis. We have demonstrated that combination of metformin with lexatumumab or TRAIL augments response to TRAIL therapy and reduce cancer cell viability via induction of apoptosis and inhibiting long-term survival of three different metastatic TNBC cell lines. Intriguingly, metformin treatment also sensitized transformed MCF10A-RasV12 cells, but not untransformed MCF10A-Vector cells, to TRAIL agonist therapy. This effect was associated with reduction of X-linked Inhibitor of Apoptosis Protein (XIAP) levels after metformin treatment. Similar to metformin treatment, inhibition of XIAP by small interfering RNA sensitized breast cancer cells to TRAIL-induced apoptosis. Moreover, metformin treatment in combination with TRAIL more efficiently inhibited primary tumor growth and lung metastases in orthotopic model of TNBC. Overall, our results demonstrate that metformin treatment in combination with targeting TRAIL receptors may be a good strategy to augment the antitumor effects of TRAIL receptors agonistic therapy and provide the foundation for a clinical trial combining dietary metfomin and TRAIL agonists. Citation Format: Elena Strekalova, Dmitry Malin, Vincent Cryns. The antidiabetic drug metformin increases pro-apoptotic effect of TRAIL therapy by reducing X-linked inhibitor of apoptosis protein (XIAP) levels in triple-negative breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3849.