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DNA-PK in human malignant disorders: Mechanisms and implications for pharmacological interventions.
Pharmacology & Therapeutics ( IF 13.5 ) Pub Date : 2020-06-28 , DOI: 10.1016/j.pharmthera.2020.107617
Michaela Medová 1 , Matúš Medo 1 , Lusine Hovhannisyan 1 , Carmen Muñoz-Maldonado 1 , Daniel M Aebersold 1 , Yitzhak Zimmer 1
Affiliation  

The DNA-PK holoenzyme is a fundamental element of the DNA damage response machinery (DDR), which is responsible for cellular genomic stability. Consequently, and predictably, over the last decades since its identification and characterization, numerous pre-clinical and clinical studies reported observations correlating aberrant DNA-PK status and activity with cancer onset, progression and responses to therapeutic modalities. Notably, various studies have established in recent years the role of DNA-PK outside the DDR network, corroborating its role as a pleiotropic complex involved in transcriptional programs that operate biologic processes as epithelial to mesenchymal transition (EMT), hypoxia, metabolism, nuclear receptors signaling and inflammatory responses. In particular tumor entities as prostate cancer, immense research efforts assisted mapping and describing the overall signaling networks regulated by DNA-PK that control metastasis and tumor progression. Correspondingly, DNA-PK emerges as an obvious therapeutic target in cancer and data pertaining to various pharmacological approaches have been published, largely in context of combination with DNA-damaging agents (DDAs) that act by inflicting DNA double strand breaks (DSBs). Currently, new generation inhibitors are tested in clinical trials. Several excellent reviews have been published in recent years covering the biology of DNA-PK and its role in cancer. In the current article we are aiming to systematically describe the main findings on DNA-PK signaling in major cancer types, focusing on both preclinical and clinical reports and present a detailed current status of the DNA-PK inhibitors repertoire.



中文翻译:

人类恶性疾病中的 DNA-PK:药物干预的机制和影响。

DNA-PK 全酶是 DNA 损伤反应机制 (DDR) 的基本要素,负责细胞基因组的稳定性。因此,可以预见的是,自其鉴定和表征以来的过去几十年中,许多临床前和临床研究报告了将异常 DNA-PK 状态和活性与癌症发病、进展和对治疗方式的反应相关联的观察结果。值得注意的是,近年来各种研究已经确立了 DNA-PK 在 DDR 网络之外的作用,证实了其作为参与转录程序的多效性复合物的作用,这些转录程序操作生物过程,如上皮到间充质转化 (EMT)、缺氧、代谢、核受体信号和炎症反应。特别是像前列腺癌这样的肿瘤实体,大量的研究工作有助于绘制和描述由 DNA-PK 调控的控制转移和肿瘤进展的整体信号网络。相应地,DNA-PK 成为癌症中一个明显的治疗靶点,并且与各种药理学方法有关的数据已经发表,主要是在与通过造成 DNA 双链断裂 (DSB) 起作用的 DNA 损伤剂 (DDA) 组合的背景下。目前,新一代抑制剂正在临床试验中进行测试。近年来发表了几篇关于 DNA-PK 生物学及其在癌症中的作用的优秀评论。在本文中,我们旨在系统地描述主要癌症类型中 DNA-PK 信号传导的主要发现,

更新日期:2020-07-22
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