The CDK4/CDK6 inhibitor PD0332991 paradoxically stabilizes activated cyclin D3-CDK4/6 complexes
The CDK4/CDK6 inhibitor PD0332991 paradoxically stabilizes activated cyclin D3-CDK4/6 complexes
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DOI：
10.4161/15384101.2014.946841
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发表时间：
2014-09-15
期刊：
影响因子：
4.3
通讯作者：
Roger, Pierre P.
中科院分区：
文献类型：
--
作者：
Paternot, Sabine;Colleoni, Bianca;Roger, Pierre P.
与D型细胞周期蛋白结合的CDK 4和CDK 6是G1期细胞周期调控的主要整合子，通过启动中心抑癌基因pRb的失活磷酸化。由于其在癌症中的频繁失调，细胞周期蛋白D-CDK 4/6复合物正在成为特别有前途的治疗靶点。特异性CDK 4/6抑制剂PD 0332991目前正在越来越多的II/III期临床试验中进行测试，以对抗各种pRb-熟练的化疗耐药癌症。我们以前已经表明，PD 0332991不仅抑制CDK 4/6的活性，而且还通过磷酸化的大部分细胞周期蛋白D-CDK 4复合物的p21结合稳定的激活。在这里，我们表明，PD 0332991对细胞周期蛋白D-CDK 4/6复合物的激活有积极或消极的影响，这取决于它们与p21的结合。事实上，尽管PD 0332991抑制p21结合的CDK 4/6的磷酸化和活性，但它特异性地稳定了缺乏p21和p27的活化的细胞周期蛋白D3-CDK 4/6复合物。在消除PD 0332991后，这些活化的细胞周期蛋白D3-CDK 4/6复合物持续至少24小时，导致在没有促有丝分裂刺激的情况下进入反常的细胞周期。PD 0332991对细胞周期蛋白D3-CDK 4/6激活的这种意料之外的积极作用应在PD 0332991的临床评价中仔细评估，迄今为止，该评价仅涉及间断给药方案。
CDK4 and CDK6 bound to D-type cyclins are master integrators of G1 phase cell cycle regulations by initiating the inactivating phosphorylation of the central oncosuppressor pRb. Because of their frequent deregulation in cancer, cyclin D-CDK4/6 complexes are emerging as especially promising therapeutic targets. The specific CDK4/6 inhibitor PD0332991 is currently tested in a growing number of phase II/III clinical trials against a variety of pRb-proficient chemotherapy-resistant cancers. We have previously shown that PD0332991 inhibits not only CDK4/6 activity but also the activation by phosphorylation of the bulk of cyclin D-CDK4 complexes stabilized by p21 binding. Here we show that PD0332991 has either a positive or a negative impact on the activation of cyclin D-CDK4/6 complexes, depending on their binding to p21. Indeed, whereas PD0332991 inhibits the phosphorylation and activity of p21-bound CDK4/6, it specifically stabilized activated cyclin D3-CDK4/6 complexes devoid of p21 and p27. After elimination of PD0332991, these activated cyclin D3-CDK4/6 complexes persisted for at least 24h, resulting in paradoxical cell cycle entry in the absence of a mitogenic stimulation. This unsuspected positive effect of PD0332991 on cyclin D3-CDK4/6 activation should be carefully assessed in the clinical evaluation of PD0332991, which until now only involves discontinuous administration protocols.