Activity of M3814, an Oral DNA-PK Inhibitor, In Combination with Topoisomerase II Inhibitors in Ovarian Cancer Models. Academic Article uri icon

Overview

abstract

  • DNA-dependent protein kinase (DNA-PK) has been shown to play a crucial role in repair of DNA double-strand breaks, facilitating nonhomologous end-joining. DNA-PK inhibitors have the potential to block DNA repair and therefore enhance DNA-damaging agents. M3814 is a DNA-PK inhibitor that has shown preclinical activity in combination with DNA-damaging agents, including radiotherapy and topoisomerase II inhibitors. Here we evaluated the activity of M3814 in combination with multiple topoisomerase II inhibitors, doxorubicin, etoposide, and pegylated liposomal doxorubicin (PLD) in vivo, utilizing ovarian cancer xenografts. Using cell lines representative of P53 wild-type ovarian cancer (A2780), and P53 mutant ovarian cancer (SKOV3), cells were implanted in the flank of athymic nude female mice. Mice were treated with vehicle, M3814 alone, topoisomerase II inhibitor alone, and M3814 in combination with topoisomerase II inhibitor, and change in tumor volume over time was documented. The addition of M3814 was well tolerated. We demonstrated that M3814 shows limited efficacy as a single agent in ovarian cancer models. The combination of M3814 with PLD showed enhanced activity over PLD as a single agent. Further study of this combination is warranted.

publication date

  • December 11, 2019

Research

keywords

  • Antineoplastic Agents
  • Carcinoma, Ovarian Epithelial
  • DNA-Activated Protein Kinase
  • Ovarian Neoplasms
  • Protein Kinase Inhibitors
  • Topoisomerase II Inhibitors
  • Tumor Burden

Identity

PubMed Central ID

  • PMC6906487

Scopus Document Identifier

  • 85076477905

Digital Object Identifier (DOI)

  • 10.1038/s41598-019-54796-6

PubMed ID

  • 31827119

Additional Document Info

volume

  • 9

issue

  • 1