Pre-clinical activity of the oral DNA-PK inhibitor, peposertib (M3814), combined with radiation in xenograft models of cervical cancer

Sushmita B Gordhandas,Rachel N Grisham,Gopa Iyer,Yukio Sonoda,Kathleen N Moore,Beryl Manning-Geist,Carol Aghajanian,Christina Henson,Ginger J Gardner,M Herman Chui

doi:10.1038/s41598-021-04618-5

Abstract

DNA-dependent protein kinase (DNA-PK) plays a crucial role in repair of DNA double-strand breaks by facilitating non-homologous end-joining. Inhibitors of DNA-PK have the potential to block DNA repair and enhance DNA-damaging agents. Peposertib (M3814) is a DNA-PK inhibitor that has shown preclinical activity in combination with DNA-damaging agents, including ionizing radiation (IR) and topoisomerase II inhibitors. Here we evaluated the activity of peposertib (M3814) in combination with radiation in a mouse xenograft model of HPV-associated cervical cancer. Athymic nude female mice with established tumors derived from HeLa cells injected into the flank were treated with vehicle alone (n = 3), IR alone (n = 4), and peposertib (M38814) in combination with IR (M3814 + IR; n = 4). While IR alone was associated with a trend towards decreased tumor volume compared with untreated, only the M3814 + IR treatment arm was associated with consistent and significant reduction in tumor burden, which correlated with higher levels of γ-H2AX in tumor cells, a marker of double-strand DNA breaks. Our data support further clinical evaluation of the combination of peposertib (M38814) and IR in cervical cancer.

Highlights

DNA damage is inherent in the process of DNA replication, and repair of this damage is essential for normal cell function
To test the efficacy of peposertib (M3814) in combination with ionizing radiation (IR) we performed in vivo xenograft studies using the HeLa cell line, as a model of HPV-associated cervical cancer (HeLa)
Mice were separated into three treatment groups: vehicle alone (n = 3), IR alone (n = 4), and peposertib (M38814) in combination with IR (M3814 + IR) (n = 4) (Fig. 1)

Summary

Introduction

DNA damage is inherent in the process of DNA replication, and repair of this damage is essential for normal cell function. Zenke and colleagues evaluated the IC50 and EC50 of cervical cancer cell lines C33A, CASKI and HeLa for treatment with peposertib (M38814) alone and in combination with 3 Gy IR. Growth viability was assessed and demonstrated sensitivity of all 3 cervical cancer cell lines to peposertib (M3814) in combination with IR and evidence of synergistic affect. Additional mouse models have demonstrated that peposertib (M38814) in combination with IR has activity in colon and pancreatic c ancer[13]. These studies provide evidence that inhibition of DNA-PK sensitizes cancer cells to DSBs induced by IR. Targeting DNA damage response pathways is a potentially effective strategy for treatment of HPV-associated cervical cancer. We hypothesize that the combination of peposertib (M3814) and IR will provide cervical cancer patients with new treatment options that are both efficacious and tolerable

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