Niraparib (MK-4827), a novel poly(ADP-Ribose) polymerase inhibitor, radiosensitizes human lung and breast cancer cells

// Kathleen A. Bridges 1 , Carlo Toniatti 2 , Carolyn A. Buser 3 , Huifeng Liu 1 , Thomas A. Buchholz 4 , and Raymond E. Meyn 1 1 Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 2 IRBM/Merck Research Laboratories Rome, Italy 3 Merck Sharp & Dohme Corp., Upper Gwynedd, Pennsylvania 4 Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas Correspondence: Raymond E. Meyn, email: // Keywords : Radiation, PARP, MK-4827, DNA damage, niraparib Received : May 5, 2014 Accepted : June 7, 2014 Published : June 9, 2014 Abstract The aim of this study was to assess niraparib (MK-4827), a novel poly(ADP-Ribose) polymerase (PARP) inhibitor, for its ability to radiosensitize human tumor cells. Human tumor cells derived from lung, breast and prostate cancers were tested for radiosensitization by niraparib using clonogenic survival assays. Both p53 wild-type and p53-defective lines were included. The ability of niraparib to alter the repair of radiation-induced DNA double strand breaks (DSBs) was determined using detection of γ-H2AX foci and RAD51 foci. Clonogenic survival analyses indicated that micromolar concentrations of niraparib radiosensitized tumor cell lines derived from lung, breast, and prostate cancers independently of their p53 status but not cell lines derived from normal tissues. Niraparib also sensitized tumor cells to H 2 O 2 and converted H 2 O 2 -induced single strand breaks (SSBs) into DSBs during DNA replication. These results indicate that human tumor cells are significantly radiosensitized by the potent and selective PARP-1 inhibitor, niraparib, in the in vitro setting. The mechanism of this effect appears to involve a conversion of sublethal SSBs into lethal DSBs during DNA replication due to the inhibition of base excision repair by the drug. Taken together, our findings strongly support the clinical evaluation of niraparib in combination with radiation.