靶向核酸代谢:克服三阴性乳腺癌化疗耐药新思路
  • 三阴性乳腺癌(TBNC)常用的化疗药(阿霉素、顺铂等),会使TNBC细胞中嘧啶的合成增多
  • 传统化疗可以改变CAD(嘧啶合成过程中关键的酶)的磷酸化状态,进而影响细胞内嘧啶的合成
  • 抑制嘧啶的合成,可以恢复TNBC对传统化疗药的敏感性,其核心机制与DNA修复有关
  • 在小鼠移植瘤模型中,联合阿霉素和来氟米特(一种已经上市的用于治疗皮肤病的嘧啶合成抑制剂),可以更好地抑制TNBC的生长
  • 核苷酸代谢,或许是未来肿瘤研究和制药的热门方向
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Cancer Discovery [IF:29.497]

Adaptive Reprogramming of De Novo Pyrimidine Synthesis Is a Metabolic Vulnerability in Triple-Negative Breast Cancer

Cancer Discovery: 靶向嘧啶代谢,或可克服三阴性乳腺癌化疗耐药

10.1158/2159-8290.CD-16-0611

2017-03-02, Opinion

Abstract & Authors:展开

Abstract:收起
Chemotherapy resistance is a major barrier to the treatment of triple-negative breast cancer (TNBC), and strategies to circumvent resistance are required. Using in vitro and in vivo metabolic profiling of TNBC 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. Pharmacologic inhibition of de novo pyrimidine synthesis sensitizes TNBC 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 TNBC 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 TNBC.SIGNIFICANCE: The prognosis for patients with TNBC with residual disease after chemotherapy is poor. We find that chemotherapy agents induce adaptive reprogramming of de novo pyrimidine synthesis and show that this response can be exploited pharmacologically, using clinically approved inhibitors of de novo pyrimidine synthesis, to sensitize TNBC cells to chemotherapy. Cancer Discov; 7(4); 1-9. ©2017 AACR.

First Authors:
Kristin K Brown

Correspondence Authors:
Alex Toker,Kristin K Brown

All Authors:
Kristin K Brown,Jessica B Spinelli,John M Asara,Alex Toker

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