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

eLife

Kaiqiong Zhao¹  Yannick Audet-Delage²  Lucía Minarrieta²  Celia MT Greenwood³  Julie St-Pierre⁴  Sidong Huang⁴  Yibo Xue⁴  Catherine St-Louis⁵  Shawn McGuirk⁵  Vincent Giguère⁶  Matthew G Annis⁶  Peter M Siegel⁶  Geneviève Morin⁷  David A Patten⁸  Mathieu Vernier⁸ 

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

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

DOI  :  10.7554/eLife.65150

来源: DOAJ

【 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】

Unknown