Abstract 4830: Selective DNA-PK inhibitor, M3814, boosts p53 apoptotic response to DNA double strand breaks and effectively kills acute leukemia cells: Implications for AML therapy

M3814 is a selective inhibitor of DNA-PK in 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 inhibiting DNA-PK catalytic activity in the presence of DSB damage, M3814 disrupts a previously unrecognized negative regulatory loop between DNA-PK and ATM, leading to increased activation of the ATM pathway, including its downstream targets, CHK2 and p53. As a result, in cancer cells expressing wild-type p53, DNA-PK inhibitor strongly activates the p53 response to DSB DNA damage and its two main functions- cell cycle arrest and apoptosis. While p53 activation in p53 wild-type epithelial cancer cells causes effective cell cycle arrest, the majority of the epithelial tumors lose their ability to undergo p53 dependent apoptosis. In contrast, tumor cells from patients with acute leukemia express wild-type p53 in with preserved p53 apoptotic function, making them amenable to p53 activation approaches. Here, we investigate the therapeutic potential of M3814 in combination with DSB-inducing agents in acute leukemia cells. M3814 strongly potentiated the activity of IR in three p53 wild-type leukemia cell lines (MOLM-13, MOLT-4, MV4-11) but had minimal effect on the p53-null HL-60 and THP-1 lines. This potentiation was due to enhanced activation of the p53 pathway as demonstrated by substantially increased expression of p53 transcriptional targets, p21 and PUMA, and induction of apoptosis only in p53 wild-type cells. M3814 showed synergism in p53-dependent cell killing with the topoisomerase inhibitors, daunorubicin and idarubicin, and 2-3 fold increase in the potency of daunorubicin/cytarabine combination in p53 wild-type acute myeloid leukemia (AML) cells. Daunorubicin/cytarabine/M3814 combinations were better tolerated by CD34 + bone marrow cells harvested from healthy volunteers and tested in vitro. These results support further exploration of M3814 as a novel combination partner in the treatment of p53 wild-type AML. Citation Format: Eric Haines, Astrid Zimmermann, Frank Zenke, Andree Blaukat, Lyubomir T. Vassilev. Selective DNA-PK inhibitor, M3814, boosts p53 apoptotic response to DNA double strand breaks and effectively kills acute leukemia cells: Implications for AML therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4830.