eLife (Jun 2021)

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

  • Shawn McGuirk,
  • Yannick Audet-Delage,
  • Matthew G Annis,
  • Yibo Xue,
  • Mathieu Vernier,
  • Kaiqiong Zhao,
  • Catherine St-Louis,
  • Lucía Minarrieta,
  • David A Patten,
  • Geneviève Morin,
  • Celia MT Greenwood,
  • Vincent Giguère,
  • Sidong Huang,
  • Peter M Siegel,
  • Julie St-Pierre

Journal volume & issue
Vol. 10


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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.