Chemical Inhibition of Wild-Type p53-Induced Phosphatase 1 (WIP1/PPM1D) by GSK2830371 Potentiates the Sensitivity to MDM2 Inhibitors in a p53-Dependent Manner.
Chemical Inhibition of Wild-Type p53-Induced Phosphatase 1 (WIP1/PPM1D) by GSK2830371 Potentiates the Sensitivity to MDM2 Inhibitors in a p53-Dependent Manner.
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DOI：
10.1158/1535-7163.mct-15-0651
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发表时间：
2016-03
影响因子：
5.7
通讯作者：
Lunec J
中科院分区：
文献类型：
--
作者：
Esfandiari A;Hawthorne TA;Nakjang S;Lunec J
对MDM2抑制剂的敏感性在反应灵敏的TP53野生型细胞系和肿瘤中有很大不同。了解MDM2抑制剂敏感性的决定因素对其最佳临床应用具有重要意义。由PPM1D编码的野生型P53诱导的磷酸酶-1(WIP1)在一系列野生型肿瘤中被激活、获得/扩增，并参与P53应激反应的动态平衡。我们研究了野生型和匹配的突变型/空细胞系对PPM1D遗传状态不同的TP53细胞对Nutlin-3/RG7388±一种高选择性Wip1抑制剂GSK2830371的反应。我们还评估了GSK2830371对MDM2抑制剂诱导的p53Ser15磷酸化、p53介导的整体转录活性和细胞凋亡的影响。所研究的细胞对对单一药物GSK2830371相对不敏感。然而，非生长抑制剂量的GSK2830371显著增强了TP53野生型细胞系对MDM2抑制剂的反应，最明显的是那些含有PPM1D激活突变或拷贝数增加的细胞系(GI50最多减少5.8倍)。增强也与MDM2抑制剂诱导的细胞死亡终点显著增加相关，在此之前，Wip1负调控底物磷酸化p53Ser15显著增加，已知可增加p53的转录活性。基于微阵列的基因表达分析表明，联合治疗增加了RG7388诱导的早期P53转录靶基因的亚集。这些发现表明，有效和选择性的Wip1抑制增强了TP53野生型细胞对MDM2抑制剂的反应，特别是那些具有PPM1D激活或获得的细胞，同时强调了p53Ser15的机制重要性及其作为对这种联合方案反应的生物标记物的潜在用途。
Sensitivity to MDM2 inhibitors is widely different among responsive TP53 wild-type cell lines and tumours. Understanding the determinants of MDM2 inhibitor sensitivity is pertinent for their optimal clinical application. Wild-type p53-inducible phosphatase-1 (WIP1) encoded by PPM1D, is activated, gained/amplified in a range of TP53 wild-type malignancies and is involved in p53 stress response homeostasis. We investigated cellular growth/proliferation of TP53 wild-type and matched mutant/null cell line pairs, differing in PPM1D genetic status, in response to Nutlin-3/RG7388 ± a highly selective WIP1 inhibitor GSK2830371. We also assessed the effects of GSK2830371 on MDM2 inhibitor induced p53Ser15 phosphorylation, p53-mediated global transcriptional activity and apoptosis. The investigated cell line pairs were relatively insensitive to single agent GSK2830371. However, a non-growth inhibitory dose of GSK2830371 markedly potentiated the response to MDM2 inhibitors in TP53 wild-type cell lines, most notably in those harbouring PPM1D activating mutations or copy number gain (up to 5.8-fold decrease in GI50). Potentiation also correlated with significant increase in MDM2 inhibitor induced cell death endpoints which were preceded by a marked increase in a WIP1 negatively regulated substrate, phosphorylated p53Ser15, known to increase p53 transcriptional activity. Microarray-based gene expression analysis showed that the combination treatment increases the subset of early RG7388 induced p53-transcriptional target genes. These findings demonstrate that potent and selective WIP1 inhibition potentiates the response to MDM2 inhibitors in TP53 wild-type cells, particularly those with PPM1D activation or gain, while highlighting the mechanistic importance of p53Ser15 and its potential use as a biomarker for response to this combination regimen.