Resistance to different anthracycline chemotherapeutics elicits distinct and actionable primary metabolic dependencies in breast cancer

eLife

Vincent Giguère¹  Yibo Xue¹  Shawn McGuirk¹  Geneviève Morin¹  Sidong Huang¹  Julie St-Pierre²  Yannick Audet-Delage³  Catherine St-Louis³  Lucía Minarrieta³  David A Patten³  Kaiqiong Zhao⁴  Celia MT Greenwood⁵  Mathieu Vernier⁶  Matthew G Annis⁷  Peter M Siegel⁷ 

[1] 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;Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Canada;Ottawa Institute of Systems Biology, Ottawa, Canada;Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Canada;Lady Davis Institute, Jewish General Hospital, 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;Goodman Cancer Research Centre, McGill University, Montreal, Canada;Goodman Cancer Research Centre, McGill University, Montreal, Canada;Department of Medicine, Faculty of Medicine, McGill University, Montreal, Canada;

关键词: breast cancer;    anthracyclines;    metabolomics;    therapeutic resistance;    bioenergetics;    PGC-1;    Human;    Mouse;   

DOI  :  10.7554/eLife.65150

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY