DNA-PK inhibitor peposertib enhances p53-dependent cytotoxicity of DNA double-strand break inducing therapy in acute leukemia
Open Access
- 9 June 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Scientific Reports
- Vol. 11 (1), 1-14
- https://doi.org/10.1038/s41598-021-90500-3
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.Keywords
Funding Information
- Merck KGaA
This publication has 59 references indexed in Scilit:
- Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid LeukemiaThe New England Journal of Medicine, 2013
- Chemosensitization of Cancer Cells by KU-0060648, a Dual Inhibitor of DNA-PK and PI-3KMolecular Cancer Therapeutics, 2012
- SnapShot: Extrinsic Apoptosis PathwaysCell, 2010
- Small RING Finger Proteins RBX1 and RBX2 of SCF E3 Ubiquitin Ligases: The Role in Cancer and as Cancer TargetsGenes & Cancer, 2010
- p53 loss promotes acute myeloid leukemia by enabling aberrant self-renewalGenes & Development, 2010
- The DNA-damage response in human biology and diseaseNature, 2009
- Inhibition of cell differentiation: A critical mechanism for MYC-mediated carcinogenesis?Cell Cycle, 2009
- DNA damage-induced cell death by apoptosisTrends in Molecular Medicine, 2006
- The DNA repair complex DNA-PK, a pharmacological target in cancer chemotherapy and radiotherapyPathologie Biologie, 2006
- Disruption of differentiation in human cancer: AML shows the wayNature Reviews Cancer, 2003