Targeting the cell cycle in breast cancer: towards the next phase
Targeting the cell cycle in breast cancer: towards the next phase
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DOI：
10.1080/15384101.2018.1502567
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发表时间：
2018-01-01
期刊：
影响因子：
4.3
通讯作者：
Cescon, D. W.
中科院分区：
文献类型：
--
作者：
Thu, K. L.;Soria-Bretones, I.;Cescon, D. W.
细胞周期的失调是癌症的一个标志，它使细胞无限分裂。为了支持这种恶性表型，细胞获得分子改变，废除或绕过信号通路和细胞检查点中的控制机制，这些机制通常起着防止基因组不稳定和不受控制的细胞增殖的作用。因此，细胞周期的靶向治疗一直被认为是一种很有前途的抗癌策略。直到最近，由于难以忍受的毒性和缺乏目标特异性，使用选择性抑制剂靶向细胞周期进行癌症治疗的尝试被证明是不成功的。然而，我们对恶性细胞特异性脆弱性的理解的改进揭示了癌细胞中优先靶向细胞周期的治疗窗口，并导致了临床药物的发展。在这篇综述中，我们讨论了最新一代的细胞周期靶向乳腺癌抗癌药物，包括已批准的CDK4/6抑制剂，以及目前正在临床试验中的TTK和PLK4抑制剂。鉴于对CDK4/6抑制剂具有获得性耐药的ER+乳腺癌的新兴人群，我们建议新的治疗途径来治疗这些患者。我们还提出了我们对未来研究方向的看法，以解决耐药性问题，并讨论了成功实施这些策略所需的机制见解。
Deregulation of the cell cycle is a hallmark of cancer that enables limitless cell division. To support this malignant phenotype, cells acquire molecular alterations that abrogate or bypass control mechanisms in signaling pathways and cellular checkpoints that normally function to prevent genomic instability and uncontrolled cell proliferation. Consequently, therapeutic targeting of the cell cycle has long been viewed as a promising anti-cancer strategy. Until recently, attempts to target the cell cycle for cancer therapy using selective inhibitors have proven unsuccessful due to intolerable toxicities and a lack of target specificity. However, improvements in our understanding of malignant cell-specific vulnerabilities has revealed a therapeutic window for preferential targeting of the cell cycle in cancer cells, and has led to the development of agents now in the clinic. In this review, we discuss the latest generation of cell cycle targeting anti-cancer agents for breast cancer, including approved CDK4/6 inhibitors, and investigational TTK and PLK4 inhibitors that are currently in clinical trials. In recognition of the emerging population of ER+ breast cancers with acquired resistance to CDK4/6 inhibitors we suggest new therapeutic avenues to treat these patients. We also offer our perspective on the direction of future research to address the problem of drug resistance, and discuss the mechanistic insights required for the successful implementation of these strategies.