Abstract 3042: Non-covalent thioredoxin reductase inhibitors for TNBC

Abstract Triple negative breast cancer (TNBC) has the lowest 5-year mortality and lacks targeted therapeutics. Therefore, there is a need to explore more therapeutic targets and strategies. Previous research has indicated that TXNRD1 may be a relevant target in other cancers and is elevated in TNBC and high levels of TXNRD1 and TXNRD2 correlate to lower recurrence free survival and lower overall survival (TXNRD1) and has emerged as a possible therapeutic target.The thioredoxin system includes thioredoxin reductase (TXNRD) and thioredoxin (Trx). TXNRD takes electrons from NADPH to reduce the disulfide bond in thioredoxin. Reduced thioredoxin then goes on to reduce reactive oxygen species (ROS), other oxidized species, and proteins within the cell. This system is critical in maintaining intracellular redox homeostasis, especially in breast cancer, where tumor cells heavily rely on these detoxifying systems to balance ROS produced by the dysregulated metabolism in cancer.Previous research has shown that targeting the thioredoxin reductase system using FDA approved auranofin has anticancer activity. However, auranofin is a covalent inhibitor of thioredoxin reductases, inhibits isoforms indiscriminately, and has significant side effects.Here, we show that new non-covalent inhibitors developed to target thioredoxin glutathione reductase in Schistosoma mansoni, also inhibit human TXNRD as demonstrated through fluorescent biochemical assays and qPCR of TXNRD related genes. Additionally, these non-covalent TXNRD inhibitors (TXNRD(i)s) show anti-cancer activity in both in vitro and in vivo TNBC models. Treatment with these TXNRD(i)s reduces viability and collagen invasion in TNBC cell lines. Similarly, knocking down TXNRD1 reduces TNBC cell invasion through collagen. Indicating TXNRD1 may be the primary target. In a TNBC xenograft, these TXNRD(i)s inhibit primary tumor growth, alter gene expression levels of multiple epithelial-mesenchymal transition (EMT) associated genes within the tumor and inflammatory markers within the host animal. These data also indicate there is a potential use of these inhibitors in a metastatic model that remains to be explored.Overall, we have shown that these TXNRD(i)s inhibit human TXNRD, have anti-cancer effects in TNBC in vitro and in vivo, inhibit collagen invasion, and alter EMT and inflammatory gene expression levels. Further research on the downstream mechanisms and optimization of these TXNRD(i)s is needed. Citation Format: Brenna Flowers, Abigail Rullo, Pavel Petukhov, Irida Kastrati. Non-covalent thioredoxin reductase inhibitors for TNBC [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 3042.