DNA-PK inhibitor peposertib enhances p53-dependent cytotoxicity of DNA double-strand break inducing therapy in acute leukemia
Abstract 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...
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doaj-36b7c6a88d6e4d8b9b33159cd731cb9e2021-06-13T11:43:40ZengNature Publishing GroupScientific Reports2045-23222021-06-0111111410.1038/s41598-021-90500-3DNA-PK inhibitor peposertib enhances p53-dependent cytotoxicity of DNA double-strand break inducing therapy in acute leukemiaEric Haines0Yuki Nishida1Michael I. Carr2Rafael Heinz Montoya3Lauren B. Ostermann4Weiguo Zhang5Frank T. Zenke6Andree Blaukat7Michael Andreeff8Lyubomir T. Vassilev9Translational Innovation Platform Oncology and Immuno-Oncology, EMD Serono Research & Development Institute, IncSection of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer CenterTranslational Innovation Platform Oncology and Immuno-Oncology, EMD Serono Research & Development Institute, IncSection of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer CenterSection of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer CenterSection of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer CenterTranslational Innovation Platform Oncology and Immuno-Oncology, Merck KGaATranslational Innovation Platform Oncology and Immuno-Oncology, Merck KGaASection of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer CenterTranslational Innovation Platform Oncology and Immuno-Oncology, EMD Serono Research & Development Institute, IncAbstract 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.https://doi.org/10.1038/s41598-021-90500-3 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Eric Haines Yuki Nishida Michael I. Carr Rafael Heinz Montoya Lauren B. Ostermann Weiguo Zhang Frank T. Zenke Andree Blaukat Michael Andreeff Lyubomir T. Vassilev |
spellingShingle |
Eric Haines Yuki Nishida Michael I. Carr Rafael Heinz Montoya Lauren B. Ostermann Weiguo Zhang Frank T. Zenke Andree Blaukat Michael Andreeff Lyubomir T. Vassilev DNA-PK inhibitor peposertib enhances p53-dependent cytotoxicity of DNA double-strand break inducing therapy in acute leukemia Scientific Reports |
author_facet |
Eric Haines Yuki Nishida Michael I. Carr Rafael Heinz Montoya Lauren B. Ostermann Weiguo Zhang Frank T. Zenke Andree Blaukat Michael Andreeff Lyubomir T. Vassilev |
author_sort |
Eric Haines |
title |
DNA-PK inhibitor peposertib enhances p53-dependent cytotoxicity of DNA double-strand break inducing therapy in acute leukemia |
title_short |
DNA-PK inhibitor peposertib enhances p53-dependent cytotoxicity of DNA double-strand break inducing therapy in acute leukemia |
title_full |
DNA-PK inhibitor peposertib enhances p53-dependent cytotoxicity of DNA double-strand break inducing therapy in acute leukemia |
title_fullStr |
DNA-PK inhibitor peposertib enhances p53-dependent cytotoxicity of DNA double-strand break inducing therapy in acute leukemia |
title_full_unstemmed |
DNA-PK inhibitor peposertib enhances p53-dependent cytotoxicity of DNA double-strand break inducing therapy in acute leukemia |
title_sort |
dna-pk inhibitor peposertib enhances p53-dependent cytotoxicity of dna double-strand break inducing therapy in acute leukemia |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2021-06-01 |
description |
Abstract 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. |
url |
https://doi.org/10.1038/s41598-021-90500-3 |
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