Activity of M3814, an oral DNA-PK inhibitor, in combination with topoisomerase II inhibitors in ovarian cancer models Journal Article

   


Authors: Wise, H. C.; Iyer, G. V.; Moore, K.; Temkin, S. M.; Gordon, S.; Aghajanian, C.; Grisham, R. N.
Article Title: Activity of M3814, an oral DNA-PK inhibitor, in combination with topoisomerase II inhibitors in ovarian cancer models
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. © 2019, The Author(s).
Journal Title: Scientific Reports
Volume: 9
ISSN: 2045-2322
Publisher: Nature Publishing Group  
Date Published: 2019-01-01
Start Page: 18882
Language: English
DOI: 10.1038/s41598-019-54796-6
PUBMED: 31827119
PROVIDER: scopus
PMCID: PMC6906487
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85076477905&doi=10.1038%2fs41598-019-54796-6&partnerID=40&md5=d733e7ca3a4ea7cdee17cad7cb14160f
Notes: Article -- Source: Scopus
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MSK Authors
  1. Gopakumar Vasudeva Iyer
    342 Iyer
  2. Rachel Nicole Grisham
    169 Grisham
  3. Carol A Aghajanian
    607 Aghajanian
  4. Hannah Christina Wise
    12 Johnsen
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