MK-4827, a PARP-1/-2 inhibitor, strongly enhances response of human lung and breast cancer xenografts to radiation
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The poly-(ADP-ribose) polymerase (PARP) inhibitor, MK-4827, is a novel potent, orally bioavailable PARP-1 and PARP-2 inhibitor currently in phase I clinical trials for cancer treatment. No preclinical data currently exist on the combination of MK-4827 with radiotherapy. The current study examined combined treatment efficacy of MK-4827 and fractionated radiotherapy using a variety of human tumor xenografts of differing p53 status: Calu-6 (p53 null), A549 (p53 wild-type [wt]) and H-460 (p53 wt) lung cancers and triple negative MDA-MB-231 human breast carcinoma. To mimic clinical application of radiotherapy, fractionated radiation (2 Gy per fraction) schedules given once or twice daily for 1 to 2 weeks combined with MK-4827, 50 mg/kg once daily or 25 mg/kg twice daily, were used. MK-4827 was found to be highly and similarly effective in both radiation schedules but maximum radiation enhancement was observed when MK-4827 was given at a dose of 50 mg/kg once daily (EF = 2.2). MK-4827 radiosensitized all four tumors studied regardless of their p53 status. MK-4827 reduced PAR levels in tumors by 1 h after administration which persisted for up to 24 h. This long period of PARP inhibition potentially adds to the flexibility of design of future clinical trials. Thus, MK-4827 shows high potential to improve the efficacy of radiotherapy.
KeywordsPoly-(ADP-ribose) inhibitor MK-4827 Radiation Lung and breast tumor xenografts
This study was sponsored by a Laboratory Study Agreement with Merck Sharp & Dohme Corp.
Conflict of Interest
Authors Anjili Mathur, Carolyn Buser-Doepner and Carlo Toniatti are current or former employees of Merck Sharp & Dohme Corp.
All other authors declare that they have no conflict of interest.
- 14.Comen EA, Robson M (2010) Inhibition of poly(ADP)-ribose polymerase as a therapeutic strategy for breast cancer. Oncology (Williston Park) 24(1):55–62Google Scholar
- 21.Noël G, Godon C, Fernet M, Giocanti N, Mégnin-Chanet F, Favaudon V (2006) Radiosensitization by the poly(ADP-ribose) polymerase inhibitor 4-amino-1,8-naphthalimide is specific of the S phase of the cell cycle and involves arrest of DNA synthesis. Mol Cancer Ther 5(3):564–574PubMedCrossRefGoogle Scholar
- 33.Sandhu S, Wenham R, Wilding G, McFadden M, Sun L, Toniatti C, Stroh M, Carpenter C, De Bono J, Schelman W (2010) First-in-human trial of a poly(ADP-ribose) polymerase (PARP) inhibitor MK-4827 in advanced cancer patients (pts) with antitumor activity in BRCA-deficient and sporadic ovarian cancers. ASCO Annual Meeting, Chicago, IL, USA (2010):Abs 3001Google Scholar