Abstract 6215: Peposertib, a DNA-PK inhibitor, enhances the antitumor efficacy of anthracyclines in triple-negative breast cancer models in vitro and in vivo

Abstract

Abstract Background: Triple-negative breast cancer (TNBC) is the most lethal breast cancer subtype, exhibiting poor response rates toward current chemotherapy regimens and lacking additional effective treatment options. Approximately 30% of patients with TNBC respond well to anthracycline/taxane-based standard-of-care chemotherapy regimens. However, remaining patients demonstrate limited improvements in clinical outcomes, highlighting the critical need for effective strategies to improve anthracycline/taxane-based chemotherapy (1, 2). DNA-dependent protein kinase (DNA-PK), a member of the phosphoinositide 3-kinase-related kinase protein family, promotes nonhomologous end joining (NHEJ) as part of the DNA damage response. Peposertib is a potent, selective, and orally bioavailable DNA-PK inhibitor that strongly potentiates the antitumor effects of ionizing radiation and DNA double-strand break-inducing agents, including anthracyclines, in preclinical models. Here we report the synergistic antitumor effects of peposertib combined with topoisomerase II (TOPO II) inhibitors, particularly anthracyclines, in TNBC models in vitro and in vivo. Methodology: Combinations of peposertib with TOPO II inhibitors were evaluated in TNBC cell lines by viability assays, immunoblotting, and flow cytometry. Gene expression analysis was performed using the nCounter PanCancer pathways panel and results were confirmed by quantitative polymerase chain reaction (qPCR). In vivo efficacy was assessed in cell-line derived and patient-derived xenograft models. Results: When administered in combination with doxorubicin, epirubicin, and etoposide, peposertib exhibited synergistic antiproliferative activity in TNBC cell lines in vitro. The downstream analysis of pharmacodynamic biomarkers revealed induction of NHEJ mediated repair upon TOPO II inhibitor treatment and provided mechanistic insights into the synergistic antitumor effects of peposertib combined with TOPO II inhibitors. Furthermore, this combination treatment induced ataxia telangiectasia mutated (ATM)-dependent compensatory signaling and inflammatory responses, potentially creating a proinflammatory tumor microenvironment. To evaluate whether peposertib enhanced the antitumor effects of TOPO II inhibitors in vivo, we established a well-tolerated preclinical treatment schedule for the combined use of peposertib and pegylated liposomal doxorubicin, which was capable of achieving tumor regression in patient- and cell line-derived xenograft models of TNBC. Conclusion: Our findings suggest that cotreatment with the DNA-PK inhibitor peposertib can enhance the efficacy of anthracycline/TOPO II-based chemotherapies. This work was supported by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945). 1) Davison C et al. NPJ Breast Cancer. 2021;7(1):38. 2) Bianchini G et al. Nat Rev Clin Oncol. 2016;13(11):674-690. Citation Format: Steffie Revia, Christian Sirrenberg, Antonia Schach, Astrid Zimmermann, Frank T. Zenke, Joachim Albers. Peposertib, a DNA-PK inhibitor, enhances the antitumor efficacy of anthracyclines in triple-negative breast cancer models in vitro and in vivo. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6215.