Abstract 3421: Differential potentiation of temozolomide and camptothecin by the PARP inhibitors olaparib and veliparib in relationship with their PARP-DNA trapping abilities, and lack of impact of PARP inhibitors on cisplatin activity.

Abstract We recently showed that poly(ADP-ribose) polymerase (PARP) inhibitors act by a novel allosteric mechanism of action that involves the trapping of PARP-DNA complexes in addition to their previously established NAD-competitive catalytic inhibitory mechanism). We also demonstrated that PARP inhibitors differ in their ability to trap PARP-DNA complexes, with olaparib being more effective than veliparib in spite of their comparable potency as catalytic PARP inhibitors). Here, by using PARP knockout cells, olaparib and veliparib, we tested the role of PARP trapping in the potentiating effect of PARP inhibitors with the alkylating agent temozolomide and the topoisomerase I inhibitor, camptothecin. Using isogenic chicken DT40 cells, we show that PARP-dependent potentiation of temozolomide is markedly greater for olaparib than veliparib, and goes beyond knocking out PARP-1. On the other hand, in the case of camptothecin, knocking out PARP-1 has a greater effect than veliparib or olaparib. In human DU145 prostate cancer and SF295 glioblastoma cells, olaparib is markedly more potent than veliparib in potentiating the cytotoxicity of temozolomide whereas both olaparib and veliparib are almost comparable in the case of camptothecin. By measuring cellular PARP-DNA complexes), we find that in the case of temozolomide, olaparib is a least 10-fold more potent than veliparib at trapping PARP-DNA complexes. On the other hand, in the case of camptothecin, neither olaparib nor veliparib produced detectable trapping of PARP-DNA complexes. Finally, olaparib fails to sensitize DT40, DU145 or SF295 cells to cisplatin and does not induce detectable PARP-DNA complexes in cisplatin-treated cells. These results suggest that, in the case of temozolomide, olaparib trapping of PARP-DNA complexes is more toxic than inactivating PARP catalytic activity, which is not the case for topoisomerase I-induced DNA damage, where catalytic inactivation of PARP appears to be the sole enhancing mechanism. Citation Format: Yves G. Pommier, Junko Murai. Differential potentiation of temozolomide and camptothecin by the PARP inhibitors olaparib and veliparib in relationship with their PARP-DNA trapping abilities, and lack of impact of PARP inhibitors on cisplatin activity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3421. doi:10.1158/1538-7445.AM2013-3421