Clinical CDK4/6 inhibitors induce selective and immediate dissociation of p21 from cyclin D-CDK4 to inhibit CDK2.
Clinical CDK4/6 inhibitors induce selective and immediate dissociation of p21 from cyclin D-CDK4 to inhibit CDK2.
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DOI：
10.1038/s41467-021-23612-z
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发表时间：
2021-06-07
影响因子：
16.6
通讯作者：
Meyer T
中科院分区：
文献类型：
--
作者：
Pack LR;Daigh LH;Chung M;Meyer T
自从发现细胞周期蛋白依赖性激酶 (CDK) 作为增殖驱动因素以来，它们一直被认为是治疗靶点。 CDK4/6 小分子抑制剂在临床试验中用于治疗多种癌症类型并进行了测试。尽管 CDK4/6 抑制剂具有临床重要性，但人们对 CDK4/6 复合物如何影响 CDK4/6 复合物（结合细胞周期蛋白和 p21 等抑制性蛋白）的稳定性知之甚少。我们开发了一种检测方法来监测细胞核内 CDK 复合物的稳定性。出乎意料的是，用 CDK4/6 抑制剂（palbociclib、ribociclib 或 abemaciclib）治疗会立即选择性地将 p21 与 CDK4 解离，但不会与 CDK6 复合物解离。这种效应介导 p21 而非 p27 重新分布对 CDK2 活性的间接抑制。我们的工作表明，CDK4/6 抑制剂具有两种作用：通过 CDK4 复合物中的 p21 置换对 CDK2 进行非催化抑制，以及不依赖于 p21 的 CDK4/6 催化抑制。通过将非催化置换范围扩大到含有 p27 和 CDK6 的复合物，下一代 CDK4/6 抑制剂可能会提高疗效并克服耐药机制。临床 CDK4/6 抑制剂用于治疗多种癌症类型并经过测试。在此，作者确定这些药物以两种方式发挥作用，一种是已知的抑制激酶活性的催化作用，另一种是新发现的非催化作用，用于从 CDK4 而非 CDK6 复合物中取代 CDK 抑制剂 p21。
Since their discovery as drivers of proliferation, cyclin-dependent kinases (CDKs) have been considered therapeutic targets. Small molecule inhibitors of CDK4/6 are used and tested in clinical trials to treat multiple cancer types. Despite their clinical importance, little is known about how CDK4/6 inhibitors affect the stability of CDK4/6 complexes, which bind cyclins and inhibitory proteins such as p21. We develop an assay to monitor CDK complex stability inside the nucleus. Unexpectedly, treatment with CDK4/6 inhibitors—palbociclib, ribociclib, or abemaciclib—immediately dissociates p21 selectively from CDK4 but not CDK6 complexes. This effect mediates indirect inhibition of CDK2 activity by p21 but not p27 redistribution. Our work shows that CDK4/6 inhibitors have two roles: non-catalytic inhibition of CDK2 via p21 displacement from CDK4 complexes, and catalytic inhibition of CDK4/6 independent of p21. By broadening the non-catalytic displacement to p27 and CDK6 containing complexes, next-generation CDK4/6 inhibitors may have improved efficacy and overcome resistance mechanisms. Clinical CDK4/6 inhibitors are used and tested to treat a variety of cancer types. Here, the authors identify that these drugs work in two ways, a known catalytic role to inhibit kinase activity and a newly discovered noncatalytic role to displace CDK inhibitor p21 from CDK4 but not CDK6 complexes.
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影响因子：
10.5
作者：
LaBaer, J;Garrett, MD;Harlow, E
通讯作者：
Harlow, E
影响因子：
16.6
作者：
Liu C;Konagaya Y;Chung M;Daigh LH;Fan Y;Yang HW;Terai K;Matsuda M;Meyer T
通讯作者：
Meyer T
影响因子：
64.8
作者：
LUO, Y;HURWITZ, J;MASSAGUE, J
通讯作者：
MASSAGUE, J
DOI：
10.4161/cc.8.7.8042
发表时间：
2009-04-01
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Hahn AT;Jones JT;Meyer T
通讯作者：
Meyer T
影响因子：
64.5
作者：
Cappell SD;Chung M;Jaimovich A;Spencer SL;Meyer T
通讯作者：
Meyer T