Abstract 4441: Specific OXPHOS inhibitors can overcome chemoresistance of triple negative breast cancer

Abstract Recently, we and others have shown that drug-resistant malignancies are characterized by higher levels of mitochondrial oxidative phosphorylation (OXPHOS) compared to chemotherapy-responsive tumors. Specifically, we used cisplatin- and cyclophosphamide-resistant triple-negative breast cancer cells and corresponding xenograft models to show that the chemoresistant phenotype is characterized by a higher oxygen consumption rate and higher metastatic potential compared to its chemosensitive counterpart. We hypothesized that OXPHOS inhibitors may resensitize chemoresistant cells to anticancer therapy. Given the endosymbiotic origin of mitochondria from alphaproteobacteria, we analyzed OXPHOS inhibitors among hundreds of antimicrobial agents and selected several that specifically target chemoresistant cancer cells. Experiments in nude mice confirmed the efficacy of these compounds against tumors derived from chemoresistant cells. In addition, we performed proteomic profiling and identified several mechanisms of action of these chemicals, including enhancement of oxidative stress, induced mitophagy, and suppression of metalloproteinase activity. Furthermore, we confirmed the synergistic effects of individual antibactericidal drugs and chemotherapeutic agents and suggest that this alternative approach should be considered for the treatment of OXPHOS-dependent chemoresistant tumors. Citation Format: Cemile Uslu, Eda Kapan, Etna Abad, Alex Lyakhovich. Specific OXPHOS inhibitors can overcome chemoresistance of triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4441.