Synergistic activity of DNA damage response kinase inhibitors in combination with the targeted alpha therapy radium-223 dichloride for metastatic castration-resistant prostate cancer

V. Dunne, T. Wright, F. Liberal, K. Prise
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Abstract

Radium-223 dichloride (Ra-223, Xofigo®) is the first approved α-particle-emitting radionuclide for the treatment of symptomatic bone metastases in patients with castration-resistant prostate cancer (CRPC) with no known evidence of visceral metastases. Ra-223 is a calcium-mimetic that preferentially binds with the bone mineral hydroxyapatite at areas of high bone turnover, such as bone metastases. This highly localized radiotherapy causes a high frequency of unrepairable double-stranded DNA breaks (DSBs), resulting in a potent antitumor effect on bone metastases. Recent evidence has suggested that patients with mutations in the DNA damage response pathway (DDR), may have differential outcomes to Ra-223 treatment (1). DDR comprises a dynamic network of signalling pathways for the maintenance of genomic integrity. Ataxia telangiectasia mutated (ATM) and Rad3-related (ATR) are critical proteins which orchestrate the DDR and their activation is dependent on the type of DNA lesion. ATM is the primary responder to DSBs whilst ATR is activated by a range of lesions including single strand DNA structures at resected ends of DBSs and after replication fork stalling. In this study, we evaluated the impact of combining DDR kinase inhibitors with Ra-223 to investigate whether a greater radiosensitisation response occurs in comparison to standard X-rays in PC3 and DU145 human prostate cell lines and normal prostate epithelial RWPE-1 cells. Cell assays including clonogenic survival, DNA damage assays and flow cytometry were used to assess the effect of DDR kinase inhibitors in combination with ionising radiation. Cells were pre-treated with DDR inhibitors one-hour before exposure to 2Gy X-rays or an equivalent dose of 0.25Gy Ra-223. Our data show that, in all prostate models, DDR kinase inhibitors in combination with Ra-223 significantly enhanced radiosensitivity (p<0.005) response in comparison to combined treatment with X-rays. Furthermore, a greater quantity of residual DSBs at 24 hours post combination treatment was observed after Ra-223 exposure in comparison to X-ray exposure (p<0.001). Promisingly, this combined treatment had minimal effect on RWPE-1 normal cells. Our findings strongly support the combination of DNA damage induction by Ra-223 with DDR kinase inhibitors as a novel potential treatment option for mCRPC patients in order to improve clinical outcome. References: Velho PI, Qazi F, Hassan S, et al. Efficacy of Radium-223 in Bone-metastatic Castration-resistant Prostate Cancer with and Without Homologous Repair Gene Defects. European Urology. 2019; 76: 170-176.
DNA损伤反应激酶抑制剂联合靶向治疗镭-223二氯化治疗转移性去势抵抗性前列腺癌的协同作用
镭-223二氯化(Ra-223, Xofigo®)是首个被批准用于治疗无内脏转移证据的去势抵抗性前列腺癌(CRPC)患者的症状性骨转移的α-颗粒放射核素。Ra-223是一种钙模拟物,优先与骨矿物羟基磷灰石结合在高骨转换区域,如骨转移。这种高度局部化的放射治疗引起高频率的不可修复的双链DNA断裂(DSBs),从而对骨转移产生有效的抗肿瘤作用。最近的证据表明,DNA损伤反应途径(DDR)突变的患者可能会对Ra-223治疗产生不同的结果(1)。DDR包括一个维持基因组完整性的动态信号通路网络。共济失调毛细血管扩张突变(ATM)和rad3相关(ATR)是协调DDR的关键蛋白,它们的激活依赖于DNA损伤的类型。ATM是dsb的主要应答者,而ATR被一系列病变激活,包括dbs切除末端的单链DNA结构和复制叉停止后。在这项研究中,我们评估了DDR激酶抑制剂与Ra-223联合使用的影响,以研究与标准x射线相比,PC3和DU145人前列腺细胞系和正常前列腺上皮RWPE-1细胞是否发生更大的放射致敏反应。细胞分析包括克隆存活、DNA损伤和流式细胞术来评估DDR激酶抑制剂与电离辐射联合使用的效果。细胞在暴露于2Gy x射线或0.25Gy Ra-223的等效剂量前一小时用DDR抑制剂预处理。我们的数据显示,在所有前列腺模型中,与x射线联合治疗相比,DDR激酶抑制剂与Ra-223联合治疗显著增强放射敏感性(p<0.005)。此外,与x射线暴露相比,暴露于Ra-223后24小时观察到的残余dsb数量更多(p<0.001)。令人鼓舞的是,这种联合治疗对RWPE-1正常细胞的影响很小。我们的研究结果强烈支持将Ra-223与DDR激酶抑制剂联合使用作为mCRPC患者的一种新的潜在治疗选择,以改善临床结果。参考文献:Velho PI, Qazi F, Hassan S等。镭-223治疗伴有或不伴有同源修复基因缺陷的骨转移性去势抵抗性前列腺癌的疗效。欧洲泌尿外科杂志2019;76: 170 - 176。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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