Translational Innovation Platform Oncology and Immuno-Oncology, EMD Serono Research & Development Institute, Inc, Billerica, MA, USA.
Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Sci Rep. 2021 Jun 9;11(1):12148. doi: 10.1038/s41598-021-90500-3.
Peposertib (M3814) is a potent and selective DNA-PK inhibitor in early clinical development. It effectively blocks non-homologous end-joining repair of DNA double-strand breaks (DSB) and strongly potentiates the antitumor effect of ionizing radiation (IR) and topoisomerase II inhibitors. By suppressing DNA-PK catalytic activity in the presence of DNA DSB, M3814 potentiates ATM/p53 signaling leading to enhanced p53-dependent antitumor activity in tumor cells. Here, we investigated the therapeutic potential of M3814 in combination with DSB-inducing agents in leukemia cells and a patient-derived tumor. We show that in the presence of IR or topoisomerase II inhibitors, M3814 boosts the ATM/p53 response in acute leukemia cells leading to the elevation of p53 protein levels as well as its transcriptional activity. M3814 synergistically sensitized p53 wild-type, but not p53-deficient, AML cells to killing by DSB-inducing agents via p53-dependent apoptosis involving both intrinsic and extrinsic effector pathways. The antileukemic effect was further potentiated by enhancing daunorubicin-induced myeloid cell differentiation. Further, combined with the fixed-ratio liposomal formulation of daunorubicin and cytarabine, CPX-351, M3814 enhanced the efficacy against leukemia cells in vitro and in vivo without increasing hematopoietic toxicity, suggesting that DNA-PK inhibition could offer a novel clinical strategy for harnessing the anticancer potential of p53 in AML therapy.
Peposertib（M3814）是一种在早期临床开发中具有强大选择性的 DNA-PK 抑制剂。它能有效阻断 DNA 双链断裂（DSB）的非同源末端连接修复，并强烈增强电离辐射（IR）和拓扑异构酶 II 抑制剂的抗肿瘤作用。通过在存在 DNA DSB 的情况下抑制 DNA-PK 催化活性，M3814 增强了 ATM/p53 信号转导，导致肿瘤细胞中 p53 依赖性抗肿瘤活性增强。在这里，我们研究了 M3814 与诱导 DSB 的药物联合治疗白血病细胞和患者来源的肿瘤的潜力。我们发现，在存在 IR 或拓扑异构酶 II 抑制剂的情况下，M3814 增强了急性白血病细胞中的 ATM/p53 反应，导致 p53 蛋白水平及其转录活性升高。M3814 通过 p53 依赖性凋亡协同增强 p53 野生型（而非 p53 缺陷型）AML 细胞对 DSB 诱导剂的敏感性，涉及内在和外在效应途径。通过增强柔红霉素诱导的髓样细胞分化，进一步增强了抗白血病作用。此外，与柔红霉素和阿糖胞苷的固定比例脂质体制剂 CPX-351 联合使用，M3814 增强了体外和体内对白血病细胞的疗效，而不增加造血毒性，表明 DNA-PK 抑制可能为 AML 治疗中利用 p53 的抗癌潜力提供一种新的临床策略。
