Resistance to CDK2 Inhibitors Is Associated with Selection of Polyploid Cells in CCNE1-Amplified Ovarian Cancer
Resistance to CDK2 Inhibitors Is Associated with Selection of Polyploid Cells in CCNE1-Amplified Ovarian Cancer
复制标题
DOI：
10.1158/1078-0432.ccr-13-1337
复制
发表时间：
2013-11-01
影响因子：
11.5
通讯作者：
Bowtell, David D.
中科院分区：
文献类型：
--
作者：
Etemadmoghadam, Dariush;Au-Yeung, George;Bowtell, David D.
目的：细胞周期蛋白E1（CCNE 1）的扩增与乳腺癌、肺癌和其他实体癌的不良结局相关，并且是与高级别浆液性卵巢癌（HGSC）的原发性治疗失败相关的最突出的结构变体。我们先前已经表明，CCNE 1扩增的肿瘤显示出对CCNE 1抑制的扩增子依赖性敏感性。在这里，我们探索靶向CDK 2作为一种新的治疗策略，在CCNE 1扩增的癌症和机制的resistance.Experimental Design. We研究了使用RNA干扰和小分子抑制剂在SK-OV-3，OVCAR-4，OVCAR-3卵巢癌细胞系中抑制CDK 2的效果。为了鉴定耐药机制，我们衍生了OVCAR-3对CDK 2抑制剂的多个独立耐药亚系。通过基因表达和拷贝数分析、荧光激活细胞分选分析和常规核型分析对耐药细胞进行了广泛表征。此外，我们探讨了CCNE 1扩增和多倍体之间的关系，使用数据从原发tumors.Results：我们验证CDK 2作为一个治疗靶点在CCNE 1扩增的细胞显示选择性敏感性抑制，无论是基因敲低或使用小分子抑制剂。此外，我们确定了两种耐药机制，一种涉及CDK 2的上调，另一种涉及从预处理肿瘤群体中选择多倍体细胞的新机制。我们的基因组数据的分析表明，多倍体是一个功能的癌症基因组与CCNE 1 amplification.Conclusions：这些研究结果表明，细胞周期蛋白E1/CDK 2是一个重要的治疗目标，在HGSC，但耐CDK 2抑制剂可能会出现由于上调CDK 2靶蛋白和通过预先存在的细胞多倍体。(C)2013年AACR。
Purpose: Amplification of cyclin E1 (CCNE1) is associated with poor outcome in breast, lung, and other solid cancers, and is the most prominent structural variant associated with primary treatment failure in high-grade serous ovarian cancer (HGSC). We have previously shown that CCNE1-amplified tumors show amplicon-dependent sensitivity to CCNE1 suppression. Here, we explore targeting CDK2 as a novel therapeutic strategy in CCNE1-amplified cancers and mechanisms of resistance.Experimental Design: We examined the effect of CDK2 suppression using RNA interference and small-molecule inhibitors in SK-OV-3, OVCAR-4, and OVCAR-3 ovarian cancer cell lines. To identify mechanisms of resistance, we derived multiple, independent resistant sublines of OVCAR-3 to CDK2 inhibitors. Resistant cells were extensively characterized by gene expression and copy number analysis, fluorescence-activated cell sorting profiling and conventional karyotyping. In addition, we explored the relationship between CCNE1 amplification and polyploidy using data from primary tumors.Results: We validate CDK2 as a therapeutic target in CCNE1-amplified cells by showing selective sensitivity to suppression, either by gene knockdown or using small-molecule inhibitors. In addition, we identified two resistance mechanisms, one involving upregulation of CDK2 and another novel mechanism involving selection of polyploid cells from the pretreatment tumor population. Our analysis of genomic data shows that polyploidy is a feature of cancer genomes with CCNE1 amplification.Conclusions: These findings suggest that cyclinE1/CDK2 is an important therapeutic target in HGSC, but that resistance to CDK2 inhibitors may emerge due to upregulation of CDK2 target protein and through preexisting cellular polyploidy. (C) 2013 AACR.