PDLIM7 and CDH18 regulate the turnover of MDM2 during CDK4/6 inhibitor therapy-induced senescence.
PDLIM7 and CDH18 regulate the turnover of MDM2 during CDK4/6 inhibitor therapy-induced senescence.
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DOI：
10.1038/s41388-018-0332-y
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发表时间：
2018-09
期刊：
影响因子：
8
通讯作者：
Tap WD
中科院分区：
文献类型：
--
作者：
Klein ME;Dickson MA;Antonescu C;Qin LX;Dooley SJ;Barlas A;Manova K;Schwartz GK;Crago AM;Singer S;Koff A;Tap WD
CDK4/6抑制剂正被用于治疗各种人类恶性肿瘤。在分化良好和去分化的脂肪肉瘤中，它们的临床前景与其下调MDM2蛋白的能力有关。CDK4/6抑制剂处理后MDM2的下调也诱导了许多来自不同类型恶性肿瘤的培养的肿瘤细胞系从静止进入衰老。在这里，我们使用培养的人细胞系，并定义了PDLIM7和CDH18的作用，调节CDK4/6抑制剂处理的细胞中的MDM2蛋白。然后，我们使用了我们之前使用Palbociclib进行的II期试验的材料来证明CDH18蛋白的表达与疗效相关，以无进展生存期和总生存期衡量。这支持了一种假设，即从静止到衰老的生物转变与这类药物具有临床相关性。
CDK4/6 inhibitors are being used to treat a variety of human malignancies. In well-differentiated and dedifferentiated liposarcoma their clinical promise is associated with their ability to downregulate the MDM2 protein. The downregulation of MDM2 following treatment with CDK4/6 inhibitors also induces many cultured tumor cell lines derived from different types of malignancies to progress from quiescence into senescence. Here we used cultured human cell lines and defined a role for PDLIM7 and CDH18, regulating MDM2 protein in CDK4/6 inhibitor-treated cells. Materials from our previous phase II trials with palbociclib were then used to demonstrate that expression of CDH18 protein was associated with response, measured as both progression-free survival and overall survival. This supports the hypothesis that the biologic transition from quiescence to senescence has clinical relevance for this class of drugs.
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