Plk1 as a prognostic biomarker for prostate cancer

标题：PLK1作为前列腺癌的预后生物标志物 摘要 由于雄激素受体(AR)信号在前列腺癌(PCa)的发生发展中是必不可少的， 包括去势抵抗的前列腺癌(CRPC)，雄激素信号抑制物(ASI)是 成为CRPC的一线治疗药物。然而，ASIS有限的临床成功使它 迫切需要开发新的方法来治疗耐ASI的CRPC。电离辐射是另一个主要的 治疗慢性前列腺癌疗效有限的途径。奥拉帕利布是一种PARP1抑制剂，是最近开发的 用于靶向DNA修复缺陷的癌症，如BRCA突变。不幸的是，用法 奥拉帕利在CRPC中的应用受到以下事实的深刻限制：BRCA突变仅发生在低 PCA的百分比。因此，识别控制DNA损伤反应的其他关键调控因子 (DDR)具有重要意义，因为它将确定对奥拉帕利有反应的特定患者群体。 目的是确定Polo-like kinase1(Plk1)在调节DDR中的作用，并开发其独特的 奥拉帕利对耐asi的慢性前列腺癌患者疗效的影响。中心假设是Plk1 MRN(Mre11/Rad50/Nbs1)复合体的组成部分Mre11和MDC1(介体)的磷酸化 DNA损伤检查点1)，导致DNA损伤检查点提前终止，减少 DNA修复，从而提高了基于合成致死性概念的奥拉帕利布的疗效。我们的数据 显示Plk1直接磷酸化Mre11，Mre11的激活是DNA反应的第一步 Mre11的Plk1磷酸化导致从DNA损伤检查点恢复，并 减少了DNA修复。我们还表明，进一步放大DDR信号的蛋白质MDC1是Plk1 底物。我们的假设将通过追求三个具体目标来检验-(1)剖析Plk1如何 Mre11的磷酸化调节MRN复合体；(2)检测Plk1磷酸化是否影响MRN复合体 MDC1导致检查点提前终止；以及(3)确定Plk1是否为 前列腺癌的预后生物标志物。这些互补的目标将通过使用生物化学来实现 细胞培养系统与遗传策略并用的信号中间产物分析 用可诱导的小鼠模型。这项研究的基本原理是，它将探索Plk1的重要性 并检验Plk1是否可以作为预测奥拉帕利疗效的生物标志物 CRPC。这一贡献是重大的，因为如果是积极的，拟议研究的结果将支持 奥拉帕利治疗不同程度慢性前列腺癌的即刻临床试验 Plk1.这项研究具有创新性，因为它从一种新的Plk1信号通路来研究这种疾病， 挑战Plk1仅起调节有丝分裂事件功能的传统观点。这些研究 通过确定DDR的关键调节因子，为治疗提供新的范例 奥拉帕利治疗慢性前列腺癌的疗效观察

Title: Plk1 as a prognostic biomarker for prostate cancer Abstract Because androgen receptor (AR) signaling is essential for development of prostate cancer (PCa), including castration-resistant prostate cancer (CRPC), androgen signaling inhibitors (ASI) are becoming the first line treatment for CRPC. However, the limited clinical success of ASIs makes it urgent to develop new approaches to treat ASI-resistant CRPC. Ionizing radiation is another major approach to treat CRPC with limited efficacy. Olaparib, a PARP1 inhibitor, is recently developed and used to target cancers with a defect in DNA repair, such as BRCA mutations. Unfortunately, the usage of olaparib in CRPC is profoundly limited by the fact that BRCA mutations only occur in low percentages of PCa. Thus, identifying additional critical regulators that control DNA damage response (DDR) is of significance as it will identify specific patient populations who will be responsive to olaparib. The objective is to define the role of polo-like kinase 1 (Plk1) in regulating DDR and to exploit its unique impact on the efficacy of olaparib for ASI-resistant CRPC patients. The central hypothesis is that Plk1 phosphorylation of Mre11, a component of MRN (Mre11/Rad50/Nbs1) complex, and MDC1 (mediator of DNA damage checkpoint 1), leads to premature termination of DNA damage checkpoint, reduced DNA repair, thus increased olabparib efficacy based on the concept of synthetic lethality. Our data show that Plk1 directly phosphorylates Mre11, whose activation is the first step in response to DNA damage and that Plk1 phosphorylation of Mre11 leads to recovery from DNA damage checkpoint and reduced DNA repair. We also show that MDC1, a protein that further amplifies DDR signals, is a Plk1 substrate. Our hypothesis will be tested by pursuing three Specific Aims - (1) to dissect how Plk1 phosphorylation of Mre11 regulates the MRN complex; (2) to test whether Plk1 phosphorylation of MDC1 contributes to premature termination of checkpoint; and (3) to determine whether Plk1 is a prognostic biomarker for PCa. These complementary aims will be accomplished using biochemical analyses of signaling intermediates and employing both cell culture systems and genetic strategies with inducible mouse models. The rationale for the research is that it will probe the importance of Plk1 to DDR and to examine whether Plk1 can be a predictable biomarker for the efficacy of olaparib in CRPC. This contribution is significant because, if positive, the results of the proposed study will support an immediate clinical trial to compare the efficacy of olaparib in CRPC patients carrying different levels of Plk1. The research is innovative as it approaches the disease from a novel Plk1 signaling pathway, challenging the traditional view that Plk1 functions solely to regulate mitotic events. These studies provide a new paradigm for therapies by identifying the key regulator of DDR that is critical for the efficacy of olaparib in CRPC.