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.
Highlights
Etoposide has been a successful anticancer agent, used to treat a variety of malignancies since the 1980s1–4
The active DNA-PK complex is composed of a catalytic serine/threonine protein kinase (DNA-PKcs) and two heterodimeric subunits (KU80 and KU70) that bind to the double-strand break to direct the catalytic subunit to the site requiring repair[24]
We studied the effects of M3814 in combination with topoisomerase II inhibitors
Summary
Etoposide has been a successful anticancer agent, used to treat a variety of malignancies since the 1980s1–4. The active DNA-PK complex is composed of a catalytic serine/threonine protein kinase (DNA-PKcs) and two heterodimeric subunits (KU80 and KU70) that bind to the double-strand break to direct the catalytic subunit to the site requiring repair[24]. The discovery of this necessary role in DNA damage repair highlighted the potential of DNA-PK inhibitors to block DNA repair and enhance DNA-damaging agents. We hypothesized that the combination of M3814 and Top[2] inhibitors will provide ovarian cancer patients with new treatment options that are both efficacious and tolerable
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