The use of olaparib (AZD2281) potentiates SN-38 cytotoxicity in colon cancer cells by indirect inhibition of Rad51-mediated repair of DNA double-strand breaks

Potent application of topoisomerase I inhibitor plus PARP inhibitor has been suggested to be an effective strategy for cancer therapy. Reportedly, mismatch repair (MMR)–deficient colon cancer cells are sensitive to topoisomeraseIinhibitor,presumablyduetomicrosatelliteinstability(MSI)oftheMRE11locus.Weexamined the synergy of SN-38, an active metabolite of irinotecan, in combination with the PARP inhibitor olaparib in colon cancer cells showing different MMR status, such as MSI or microsatellite stable (MSS) phenotype. Treatment with SN-38 and olaparib in combination almost halved the IC50 of SN-38 for a broad spectrum of coloncancercellsindependentoftheMMRstatus.Furthermore,olaparibpotentiatedS-phase–specificdoublestrand DNA breaks (DSB) induced by SN-38, which is followed by Rad51 recruitment. siRNA-mediated knockdown of Rad51, but not Mre11 or Rad50, increased the sensitivity to olaparib and/or SN-38 treatment in colon cancer cells. In vivo study using mouse xenograft demonstrated that olaparib was effective to potentiate the antitumor effect of irinotecan. In conclusion, olaparib shows a synergistic effect in colon cancer cells in combination with SN-38 or irinotecan, potentiated by the Rad51-mediated HR pathway, irrespective of the Mre11-mediated failure of the MRN complex. Theseresults maycontribute to futureclinical trials usingPARP inhibitor plus topoisomerase I inhibitor in combination. Furthermore, the synergistic effect comprising topoisomeraseI-mediatedDNAbreakage–reunionreaction,PARPandRad51-mediatedHRpathwaysuggests the triple synthetic lethal pathways contribute to this event and are applicable as a potential target for future chemotherapy. Mol Cancer Ther; 13(5); 1170–80. � 2014 AACR.