Adaptive Reprogramming of De Novo Pyrimidine Synthesis Is a Metabolic Vulnerability in Triple-Negative Breast Cancer.
Adaptive Reprogramming of De Novo Pyrimidine Synthesis Is a Metabolic Vulnerability in Triple-Negative Breast Cancer.
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DOI：
10.1158/2159-8290.cd-16-0611
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发表时间：
2017-04
期刊：
影响因子：
28.2
通讯作者：
Toker A
中科院分区：
文献类型：
--
作者：
Brown KK;Spinelli JB;Asara JM;Toker A
化疗耐药性是治疗三阴性乳腺癌的主要障碍，需要采取策略来规避耐药性。使用三阴性乳腺癌细胞的体外和体内代谢谱，我们表明嘧啶核苷酸丰度的增加是对化疗暴露的反应。从机制上讲，化疗诱导的嘧啶核苷酸升高依赖于从头嘧啶合成途径活性的增加。嘧啶从头合成的药理学抑制通过加重DNA损伤使三阴性乳腺癌细胞对遗传毒性化疗剂敏感。此外，多柔比星和来氟米特（一种临床批准的从头嘧啶合成途径抑制剂）联合治疗可诱导三阴性乳腺癌异种移植物消退。因此，在化疗暴露后观察到的嘧啶核苷酸水平的增加代表了代谢脆弱性，其可以被利用来增强用于治疗三阴性乳腺癌的化疗的功效。
Chemotherapy resistance is a major barrier to the treatment of triple-negative breast cancer and strategies to circumvent resistance are required. Using in vitro and in vivo metabolic profiling of triple-negative breast cancer cells, we show that an increase in the abundance of pyrimidine nucleotides occurs in response to chemotherapy exposure. Mechanistically, elevation of pyrimidine nucleotides induced by chemotherapy is dependent on increased activity of the de novo pyrimidine synthesis pathway. Pharmacological inhibition of de novo pyrimidine synthesis sensitizes triple-negative breast cancer cells to genotoxic chemotherapy agents by exacerbating DNA damage. Moreover, combined treatment with doxorubicin and leflunomide, a clinically approved inhibitor of the de novo pyrimidine synthesis pathway, induces regression of triple-negative breast cancer xenografts. Thus, the increase in pyrimidine nucleotide levels observed following chemotherapy exposure represents a metabolic vulnerability that can be exploited to enhance the efficacy of chemotherapy for the treatment of triple-negative breast cancer.