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

Overview

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.

publication date

  • January 19, 2022

Research

keywords

  • DNA-Activated Protein Kinase
  • Pyridazines
  • Quinazolines
  • Uterine Cervical Neoplasms

Identity

PubMed Central ID

  • PMC8770623

Scopus Document Identifier

  • 85123088629

Digital Object Identifier (DOI)

  • 10.1158/1078-0432.CCR-20-0056

PubMed ID

  • 35046420

Additional Document Info

volume

  • 12

issue

  • 1