Department of Biochemistry, Faculty of Medicine, McGill University, Montreal, Canada; Goodman Cancer Research Centre, McGill University, Montreal, Canada
Department of Biochemistry, Faculty of Medicine, McGill University, Montreal, Canada; Goodman Cancer Research Centre, McGill University, Montreal, Canada
Goodman Cancer Research Centre, McGill University, Montreal, Canada
Kaiqiong Zhao
Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Canada; Lady Davis Institute, Jewish General Hospital, Montreal, Canada
Catherine St-Louis
Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Canada; Ottawa Institute of Systems Biology, Ottawa, Canada
Lucía Minarrieta
Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Canada; Ottawa Institute of Systems Biology, Ottawa, Canada
David A Patten
Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Canada; Ottawa Institute of Systems Biology, Ottawa, Canada
Geneviève Morin
Department of Biochemistry, Faculty of Medicine, McGill University, Montreal, Canada; Goodman Cancer Research Centre, McGill University, Montreal, Canada
Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Canada; Lady Davis Institute, Jewish General Hospital, Montreal, Canada; Department of Human Genetics, McGill University, Montreal, Canada; Gerald Bronfman Department of Oncology, Montreal, Canada
Vincent Giguère
Department of Biochemistry, Faculty of Medicine, McGill University, Montreal, Canada; Goodman Cancer Research Centre, McGill University, Montreal, Canada
Department of Biochemistry, Faculty of Medicine, McGill University, Montreal, Canada; Goodman Cancer Research Centre, McGill University, Montreal, Canada
Department of Biochemistry, Faculty of Medicine, McGill University, Montreal, Canada; Goodman Cancer Research Centre, McGill University, Montreal, Canada; Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Canada; Ottawa Institute of Systems Biology, Ottawa, Canada
Chemotherapy resistance is a critical barrier in cancer treatment. Metabolic adaptations have been shown to fuel therapy resistance; however, little is known regarding the generality of these changes and whether specific therapies elicit unique metabolic alterations. Using a combination of metabolomics, transcriptomics, and functional genomics, we show that two anthracyclines, doxorubicin and epirubicin, elicit distinct primary metabolic vulnerabilities in human breast cancer cells. Doxorubicin-resistant cells rely on glutamine to drive oxidative phosphorylation and de novo glutathione synthesis, while epirubicin-resistant cells display markedly increased bioenergetic capacity and mitochondrial ATP production. The dependence on these distinct metabolic adaptations is revealed by the increased sensitivity of doxorubicin-resistant cells and tumor xenografts to buthionine sulfoximine (BSO), a drug that interferes with glutathione synthesis, compared with epirubicin-resistant counterparts that are more sensitive to the biguanide phenformin. Overall, our work reveals that metabolic adaptations can vary with therapeutics and that these metabolic dependencies can be exploited as a targeted approach to treat chemotherapy-resistant breast cancer.
