DNA-PK inhibitor peposertib enhances p53-dependent cytotoxicity of DNA double-strand break inducing therapy in acute leukemia.
DNA-PK inhibitor peposertib enhances p53-dependent cytotoxicity of DNA double-strand break inducing therapy in acute leukemia.
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DOI：
10.1038/s41598-021-90500-3
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发表时间：
2021-06-09
影响因子：
4.6
通讯作者：
Vassilev LT
中科院分区：
文献类型：
--
作者：
Haines E;Nishida Y;Carr MI;Montoya RH;Ostermann LB;Zhang W;Zenke FT;Blaukat A;Andreeff M;Vassilev LT
培泊塞替布(M3814)是一种有效的、选择性的DNA-PK抑制剂，可用于早期临床研究。它有效地阻断了DNA双链断裂(DSB)的非同源末端连接修复，并强烈增强了电离辐射(IR)和拓扑异构酶II抑制剂的抗肿瘤作用。通过在DNA DSB存在的情况下抑制DNA-PK催化活性，M3814增强了ATM/P53信号转导，从而增强了肿瘤细胞中P53依赖的抗肿瘤活性。在这里，我们研究了M3814与DSB诱导剂联合使用在白血病细胞和一个正常患者来源的肿瘤中的治疗潜力。我们发现，在IR或拓扑异构酶II抑制剂的存在下，M3814增强了急性白血病细胞中ATM/P53的反应，导致P53蛋白水平的提高及其转录活性。M3814协同敏化野生型P53而不是P53缺陷型AML细胞对DSB诱导剂的杀伤作用，通过P53依赖的内源性和外源性效应通路诱导AML细胞死亡。通过促进柔红霉素诱导的髓系细胞分化，抗白血病作用进一步增强。此外，CPX-351和M3814与柔红霉素和阿糖胞苷的固定比例脂质体联合使用，在不增加造血毒性的情况下，在体内外提高了对白血病细胞的杀伤效果，提示DNA-PK抑制可能为在AML治疗中利用P53的抗癌潜力提供了一种新的临床策略。
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.
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