Molecular Pathways: CDK4 Inhibitors for Cancer Therapy
Molecular Pathways: CDK4 Inhibitors for Cancer Therapy
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DOI：
10.1158/1078-0432.ccr-13-1551
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发表时间：
2014-07-01
影响因子：
11.5
通讯作者：
Dickson, Mark A.
中科院分区：
文献类型：
--
作者：
Dickson, Mark A.
不受限制的生长是癌症的标志，因此细胞周期调节被破坏是常见的。CDK 4是G（1）-S转换的关键调节因子。在与细胞周期蛋白D的复合物中，CDK 4磷酸化视网膜母细胞瘤蛋白（Rb）并驱动细胞周期进展，这一过程被p16抑制。p16-CDK 4-cyclin D-Rb在大多数癌症中是异常的，因此是抗癌治疗的合理靶点。以前尝试用非选择性细胞周期蛋白依赖性激酶（CDK）抑制剂阻断CDK 4导致毒性和疗效甚微。然而，最近开发的选择性CDK 4抑制剂首次成功地靶向癌症治疗途径。三种口服选择性CDK 4抑制剂已进入临床试验：palbociclib（PD 0332991）、LEE 011和LY 2835219。CDK 4抑制剂在体外具有抗多种癌症的活性，并且在乳腺癌、淋巴瘤、肉瘤和其他肿瘤患者中显示出抗肿瘤活性。目前正在努力开发反应的生物标志物，了解潜在的耐药机制，并开发CDK 4抑制剂与化疗和其他靶向药物的合理组合。（C）2014年AACR。
Unrestrained growth is the hallmark of cancer, and disrupted cell-cycle regulation is, therefore, common. CDK4 is the key regulator of the G(1)-S transition. In complex with cyclin D, CDK4 phosphorylates retinoblastoma protein (Rb) and drives cell-cycle progression, a process inhibited by p16. The p16-CDK4-cyclin D-Rb is aberrant in the majority of cancers and is, thus, a logical target for anticancer therapy. Previous attempts to block CDK4 with nonselective cyclin-dependent kinase (CDK) inhibitors led to toxicity and little efficacy. However, the recent development of selective CDK4 inhibitors launched the first successful efforts to target the pathway for cancer therapy. Three oral selective CDK4 inhibitors have entered clinical trials: palbociclib (PD0332991), LEE011, and LY2835219. CDK4 inhibitors have in vitro activity against a broad range of cancers and in patients have shown antitumor activity in breast cancer, lymphoma, sarcoma, and other tumors. Major efforts are under way to develop biomarkers of response, understand potential mechanisms of resistance, and develop rational combinations of CDK4 inhibitors with chemotherapy and other targeted drugs. (C)2014 AACR.