Targeting the cyclin-dependent kinases (CDK) 4/6 in estrogen receptor-positive breast cancers.
Targeting the cyclin-dependent kinases (CDK) 4/6 in estrogen receptor-positive breast cancers.
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DOI：
10.1186/s13058-015-0661-5
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发表时间：
2016-02-09
期刊：
影响因子：
--
通讯作者：
Slamon DJ
中科院分区：
文献类型：
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作者：
Finn RS;Aleshin A;Slamon DJ
尽管在早期发现和治疗方面取得了重大进展，但乳腺癌仍然是妇女发病和死亡的主要原因。在过去的十年中，我们对乳腺癌分子异质性的理解已经显着扩大，细胞周期信号在乳腺癌肿瘤发生和抗雌激素抵抗中的作用也越来越受到关注。哺乳动物细胞周期由细胞周期蛋白及其相关的细胞周期蛋白依赖性激酶（CDK）伴侣之间的复杂相互作用驱动，该过程的失调是癌症的标志之一。尽管如此，广泛作用的CDK抑制剂的初步结果在很大程度上令人失望。然而，最近使用新型口服可逆CDK 4/6抑制剂Palbociclib（PD-0332991）进行的临床前和I/II期临床研究已经验证了CDK 4/6作为雌激素受体阳性（ER+）乳腺癌潜在靶点的作用。这篇综述强调了我们目前对正常和恶性乳腺组织中CDK信号传导的理解，特别关注ER+疾病中CDK 4/6抑制的最新临床进展。
Despite significant advances in early detection and treatment, breast cancer still remains a major cause of morbidity and mortality for women. Our understanding of the molecular heterogeneity of the disease has significantly expanded over the past decade and the role of cell cycle signaling in both breast cancer oncogenesis and anti-estrogen resistance has gained increasing attention. The mammalian cell cycle is driven by a complex interplay between cyclins and their associated cyclin-dependent kinase (CDK) partners, and dysregulation of this process is one of the hallmarks of cancer. Despite this, initial results with broadly acting CDK inhibitors were largely disappointing. However, recent preclinical and phase I/II clinical studies using a novel, oral, reversible CDK4/6 inhibitor, palbociclib (PD-0332991), have validated the role of CDK4/6 as a potential target in estrogen receptor-positive (ER+) breast cancers. This review highlights our current understanding of CDK signaling in both normal and malignant breast tissues, with special attention placed on recent clinical advances in inhibition of CDK4/6 in ER+ disease.