Radium-223 (223Ra) and Lutetium-177-labelled-PSMA-617 (177Lu-PSMA) are currently the only radiopharmaceutical treatments to prolong survival for patients with metastatic-castration-resistant prostate cancer (mCRPC); however, mCRPC remains an aggressive disease. Recent clinical evidence suggests patients with mutations in DNA repair genes associated with homologous recombination have a greater clinical benefit from223Ra. In this study, we aimed to determine the utility of combining DNA damage response (DDR) inhibitors to increase the therapeutic efficacy of X-rays, or223Ra. Radiobiological responses were characterised by in vitro assessment of clonogenic survival, repair of double strand breaks, cell cycle distribution, and apoptosis via PARP-1 cleavage. Here, we show that DDR inhibitors increase the therapeutic efficacy of both radiation qualities examined, which is associated with greater levels of residual DNA damage. Co-treatment of ATM or PARP inhibition with223Ra increased cell cycle arrest in the G2/M phase. In comparison, combined ATR inhibition and radiation qualities caused G2/M checkpoint abrogation. Additionally, greater levels of apoptosis were observed after the combination of DDR inhibitors with223Ra. This study identified the ATR inhibitor as the most synergistic inhibitor for both radiation qualities, supporting further pre-clinical evaluation of DDR inhibitors in combination with223Ra for the treatment of prostate cancer.
镭-223（223Ra）和镥-177标记的PSMA-617（177Lu-PSMA）是目前唯一能延长转移性去势抵抗性前列腺癌（mCRPC）患者生存期的放射性药物疗法；然而，mCRPC仍是一种侵袭性疾病。近期临床证据表明，携带同源重组相关DNA修复基因突变的患者从223Ra治疗中获得的临床获益更大。本研究旨在评估联合使用DNA损伤反应（DDR）抑制剂能否增强X射线或223Ra的治疗效果。通过体外克隆形成存活实验、双链断裂修复检测、细胞周期分布分析以及PARP-1裂解介导的细胞凋亡测定，系统表征了放射生物学效应。研究发现，DDR抑制剂能显著提升两种辐射类型的治疗效果，这与更高水平的残留DNA损伤相关。ATM或PARP抑制剂与223Ra联合处理可增强G2/M期细胞周期阻滞；相比之下，ATR抑制剂与辐射联用则导致G2/M检查点功能丧失。此外，DDR抑制剂与223Ra联用可诱导更高水平的细胞凋亡。本研究证实ATR抑制剂对两种辐射类型均具有最佳协同效应，为DDR抑制剂联合223Ra治疗前列腺癌的临床前研究提供了理论依据。
肿瘤(癌症)患者之家