An important part of understanding environmental cancer is coping with disease heterogeneity. Triple-negative breast cancer (TNBC) is a highly aggressive cancer subtype characterized by limited treatment options and the frequent development of drug resistance. This study investigated the metabolic adaptations associated with doxorubicin resistance in TNBC and explores the potential of dietary compounds as chemosensitizers to enhance treatment efficacy. We generated doxorubicin-resistant TNBC cell lines and characterized them using untargeted metabolomics. Through this, we identified significant alterations in key metabolic pathways between sensitive and resistant cells, including arginine and proline metabolism, glutathione metabolism, and beta-alanine metabolism. This diversity of metabolic targets of chemosensitizers suggest that they could be combined to target complementary metabolic processes to further enhance chemotherapeutic efficacy and reverse multi-drug resistance in TNBC. Overall, this study provides critical insights into the metabolic reprogramming associated with drug resistance in TNBC and highlights the potential of dietary polyphenols and omega-3 PUFAs as effective chemosensitizers. These findings also demonstrate the utility of using metabolic signatures to stratify tumors based on drug response or other significant clinical features.
