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 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.

• Authors: 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
• Journal: Scientific reports (Sci Rep) Vol. 11 Issue 1 Pg. 12148 (06 09 2021) ISSN: 2045-2322 [Electronic] England
• PMID: 34108527 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Kinase Inhibitors
• Pyridazines
• Quinazolines
• TP53 protein, human
• Tumor Suppressor Protein p53
• DNA-Activated Protein Kinase
• peposertib

Topics

• Animals
• Apoptosis
• Cell Proliferation
• DNA Breaks, Double-Stranded
• DNA Repair
• DNA-Activated Protein Kinase (antagonists & inhibitors)
• Gene Expression Regulation, Leukemic
• Humans
• Leukemia, Myeloid, Acute (drug therapy, metabolism, pathology)
• Male
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Phosphorylation
• Protein Kinase Inhibitors (pharmacology)
• Pyridazines (pharmacology)
• Quinazolines (pharmacology)
• Signal Transduction
• Tumor Cells, Cultured
• Tumor Suppressor Protein p53 (genetics, metabolism)
• Xenograft Model Antitumor Assays