Resistance to different anthracycline chemotherapeutics elicits distinct and actionable primary metabolic dependencies in breast cancer.
Resistance to different anthracycline chemotherapeutics elicits distinct and actionable primary metabolic dependencies in breast cancer.
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DOI：
10.7554/elife.65150
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发表时间：
2021-06-28
期刊：
影响因子：
7.7
通讯作者：
St-Pierre J
中科院分区：
文献类型：
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作者：
McGuirk S;Audet-Delage Y;Annis MG;Xue Y;Vernier M;Zhao K;St-Louis C;Minarrieta L;Patten DA;Morin G;Greenwood CM;Giguère V;Huang S;Siegel PM;St-Pierre J
化疗耐药是癌症治疗中的一个重要障碍。代谢适应已被证明为治疗抵抗的燃料；然而，关于这些变化的普遍性以及特定治疗是否会引发独特的代谢改变，人们知之甚少。利用代谢组学、转录组学和功能基因组学的组合，我们证明了阿霉素和表阿霉素这两种蒽环类药物在人类乳腺癌细胞中引起不同的原发代谢脆弱性。阿霉素耐药细胞依赖谷氨酰胺来驱动氧化磷酸化和谷胱甘肽的从头合成，而表阿霉素耐药细胞表现出显著的生物能量能力和线粒体ATP的产生。对这些不同的代谢适应的依赖体现在对阿霉素耐药的细胞和肿瘤移植瘤对丁硫氨酸亚磺胺(BSO)的敏感性增加，BSO是一种干扰谷胱甘肽合成的药物，而表柔比星耐药的细胞和肿瘤移植瘤对双胍苯福明更敏感。总体而言，我们的工作揭示了代谢适应随着治疗方法的不同而不同，这些代谢依赖性可以被用作治疗化疗耐药乳腺癌的一种有针对性的方法。
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.