CDK4/6 inhibition in breast cancer: current practice and future directions.
CDK4/6 inhibition in breast cancer: current practice and future directions.
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DOI：
10.1177/1758835918786451
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发表时间：
2018
影响因子：
4.9
通讯作者：
Goel S
中科院分区：
文献类型：
--
作者：
Pernas S;Tolaney SM;Winer EP;Goel S
细胞周期蛋白D/细胞周期蛋白依赖性激酶4和6（CDK 4/6）-视网膜母细胞瘤蛋白（RB）通路在正常乳腺上皮和乳腺癌细胞的增殖中起关键作用。在乳腺癌中抑制CDK 4/6的强有力的理由已经存在多年。然而，有效的和选择性的CDK 4/6抑制剂最近才变得可用。这些药物阻止RB肿瘤抑制因子的磷酸化，从而引起G1期癌细胞周期阻滞。CDK 4/6抑制剂已经从临床前研究迅速过渡到临床竞技场，并且三种已经被批准用于治疗晚期雌激素受体（ER）阳性乳腺癌患者，这是由于显著的临床试验结果表明无进展生存期的显著改善。ER阳性乳腺癌具有几个分子特征，可以预测其对CDK 4/6抑制剂的敏感性。随着医生在临床上使用这些药物的经验的积累，新的问题出现了：CDK 4/6抑制剂可能对其他亚型乳腺癌患者有用吗？除了内分泌治疗外，是否还有其他药物可以与CDK 4/6抑制剂有效联合？CDK 4/6抑制剂与新型免疫疗法结合是否有理由？在这篇综述中，我们不仅描述了迄今为止的临床数据，而且还介绍了CDK 4/6通路的生物学，并讨论了这些问题的答案。特别是，我们强调CDK 4和CDK 6的控制远远超过癌细胞周期，并且它们在临床中的最佳使用取决于对这些酶的不太好表征的作用的更深入的理解。
The cyclin D/cyclin-dependent kinases 4 and 6 (CDK4/6)–retinoblastoma protein (RB) pathway plays a key role in the proliferation of both normal breast epithelium and breast cancer cells. A strong rationale for inhibiting CDK4/6 in breast cancers has been present for many years. However, potent and selective CDK4/6 inhibitors have only recently become available. These agents prevent phosphorylation of the RB tumor suppressor, thereby invoking cancer cell cycle arrest in G1. CDK4/6 inhibitors have transited rapidly from preclinical studies to the clinical arena, and three have already been approved for the treatment of advanced, estrogen receptor (ER)-positive breast cancer patients on account of striking clinical trial results demonstrating substantial improvements in progression-free survival. ER-positive breast cancers harbor several molecular features that would predict their sensitivity to CDK4/6 inhibitors. As physicians gain experience with using these agents in the clinic, new questions arise: are CDK4/6 inhibitors likely to be useful for patients with other subtypes of breast cancer? Are there other agents that could be effectively combined with CDK4/6 inhibitors, beyond endocrine therapy? Is there a rationale for combining CDK4/6 inhibitors with novel immune-based therapies? In this review, we describe not only the clinical data available to date, but also the biology of the CDK4/6 pathway and discuss answers to these questions. In particular, we highlight that CDK4 and CDK6 govern much more than the cancer cell cycle, and that their optimal use in the clinic depends on a deeper understanding of the less well characterized effects of these enzymes.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
4.3
作者：
Dean, Jeffry L.;McClendon, A. Kathleen;Knudsen, Erik S.
通讯作者：
Knudsen, Erik S.
影响因子：
50.3
作者：
Gong, Xueqian;Litchfield, Lacey M.;Buchanan, Sean G.
通讯作者：
Buchanan, Sean G.
影响因子：
51.1
作者：
Finn, Richard S.;Crown, John P.;Slamon, Dennis J.
通讯作者：
Slamon, Dennis J.
影响因子：
45.3
作者：
Goetz, Matthew P.;Toi, Masakazu;Di Leo, Angelo
通讯作者：
Di Leo, Angelo