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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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/36b7c6a88d6e4d8b9b33159cd731cb9e
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spelling	oai:doaj.org-article:36b7c6a88d6e4d8b9b33159cd731cb9e2021-12-02T14:58:20ZDNA-PK inhibitor peposertib enhances p53-dependent cytotoxicity of DNA double-strand break inducing therapy in acute leukemia10.1038/s41598-021-90500-32045-2322https://doaj.org/article/36b7c6a88d6e4d8b9b33159cd731cb9e2021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-90500-3https://doaj.org/toc/2045-2322Abstract 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.Eric HainesYuki NishidaMichael I. CarrRafael Heinz MontoyaLauren B. OstermannWeiguo ZhangFrank T. ZenkeAndree BlaukatMichael AndreeffLyubomir T. VassilevNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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
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.
format	article
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
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 Portfolio
publishDate	2021
url	https://doaj.org/article/36b7c6a88d6e4d8b9b33159cd731cb9e
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DNA-PK inhibitor peposertib enhances p53-dependent cytotoxicity of DNA double-strand break inducing therapy in acute leukemia

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