Attenuation of the Retinoblastoma Pathway in Pancreatic Neuroendocrine Tumors Due to Increased Cdk4/Cdk6
Attenuation of the Retinoblastoma Pathway in Pancreatic Neuroendocrine Tumors Due to Increased Cdk4/Cdk6
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DOI：
10.1158/1078-0432.ccr-11-3264
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发表时间：
2012-09-01
影响因子：
11.5
通讯作者：
Harris, Chris R.
中科院分区：
文献类型：
--
作者：
Tang, Laura H.;Contractor, Tanupriya;Harris, Chris R.
目的：在小鼠中，破坏视网膜母细胞瘤肿瘤抑制通路的遗传变化通常导致胰腺神经内分泌肿瘤（Pan-NET）。相反，在患有这种疾病的人类中，即使在全基因组测序研究中，也很少检测到视网膜母细胞瘤途径基因的突变。在这项研究中，我们仔细研究了视网膜母细胞瘤通路在人类泛NETs.Experimental Design中的作用：92例患者的泛NET肿瘤进行了视网膜母细胞瘤通路标记物的免疫组化染色。为了寻找视网膜母细胞瘤途径基因的扩增，对来自26个肿瘤的基因组DNA进行拷贝数分析。最后，一个小分子活化剂的视网膜母细胞瘤通路进行了测试的影响，对两个泛NET细胞line.Results的生长：大多数肿瘤表达大量的Cdk 4或其伴侣蛋白细胞周期蛋白D1。在表达高水平Cdk 4或细胞周期蛋白D1的肿瘤中存在大量磷酸化Rb 1。Cdk 4或类似激酶基因Cdk 6的拷贝数在19%的肿瘤中增加。人泛NET细胞系QGP 1的生长被抑制在异种移植小鼠模型的Cdk 4/6抑制剂，PD 0332991，它重新激活的视网膜母细胞瘤pathway.Conclusions：失活的视网膜母细胞瘤途径，表明大多数泛NET。Cdk 4和Cdk 6的基因扩增和过表达表明，Pan-NET患者可能对正在进入临床试验的Cdk 4/6抑制剂有强烈反应。临床癌症研究; 18（17）; 4612-20。(C)2012年AACR。
Purpose: In mice, genetic changes that inactivate the retinoblastoma tumor suppressor pathway often result in pancreatic neuroendocrine tumors (Pan-NETs). Conversely, in humans with this disease, mutations in genes of the retinoblastoma pathway have rarely been detected, even in genome-wide sequencing studies. In this study, we took a closer look at the role of the retinoblastoma pathway in human Pan-NETs.Experimental Design: Pan-NET tumors from 92 patients were subjected to immunohistochemical staining for markers of the retinoblastoma pathway. To search for amplifications of retinoblastoma pathway genes, genomic DNAs from 26 tumors were subjected to copy number analysis. Finally, a small-molecule activator of the retinoblastoma pathway was tested for effects on the growth of two Pan-NET cell lines.Results: A majority of tumors expressed high amounts of Cdk4 or its partner protein cyclin D1. High amounts of phosphorylated Rb1 were present in tumors that expressed high levels of Cdk4 or cyclin D1. The copy numbers of Cdk4 or the analogous kinase gene Cdk6 were increased in 19% of the tumors. Growth of the human Pan-NET cell line QGP1 was inhibited in a xenograft mouse model by the Cdk4/6 inhibitor, PD 0332991, which reactivates the retinoblastoma pathway.Conclusions: Inactivation of the retinoblastoma pathway was indicated for most Pan-NETs. Gene amplification and overexpression of Cdk4 and Cdk6 suggests that patients with Pan-NETs may respond strongly to Cdk4/6 inhibitors that are entering clinical trials. Clin Cancer Res; 18(17); 4612-20. (C) 2012 AACR.