Abstract PL05-04: PARP trapping versus PARP catalytic inhibition and coupling with TDP1

Abstract

Abstract The five clinical PARP inhibitors (veliparib, olaparib, niraparib, rucaparib and talazoparib) are potent submicromolar competitive NAD+ inhibitors for PARP1 and PARP2, thereby blocking PARylation reactions [i.e. formation of poly(ADPribose) polymers]. In addition, PARP trapping, which determines the anticancer activity of PARP inhibitor as single agents, is drug-specific, and PARP inhibitors can be ranked according to their PARP trapping potency: talazoparib >> niraparib ≈ olaparib ≈ rucaparib > veliparib. We will review evidence that PARP trapping is the primary cytotoxic mechanism of PARP inhibitors as single agents and that cancer-specific DNA repair alterations as well as SLFN11 expression determine the cytotoxicity of trapped PARP-DNA complexes in cancers beyond BRCA inactivation. Used in combination in cellular models, PARP inhibitors are highly synergistic with alkylating agent (temozolomide or methyl methanesulfonate) and topoisomerase I (Top1) inhibitors (camptothecin and its clinical derivatives (topotecan and irinotecan) and the non-camptothecin indenoisoquinoline Top1 inhibitors in clinical development (LMP400, LMP776 and LMP744). Both alkylating agents and Top1 inhibitors induce DNA single-strand breaks sensed by PARP. Yet, the molecular mechanisms of synergy are different. For alkylating agents (temozolomide and MMS), both PARP trapping and PARylation inhibition account for the synergy, whereas for Top1 inhibitors, there is no involvement of PARP trapping and it is PARylation inhibition that deters the coupling of PARP with the repair enzyme, tyrosyl-DNA phosphodiesterase, TDP1. We will review the molecular pharmacology differences between PARP inhibitors as single agents and the rationale for choosing among different PARP inhibitors in combination with alkylating agents or Top1 inhibitors based on trapping vs. catalytic inhibition. Citation Format: Yves G. Pommier, Junko Murai. PARP trapping versus PARP catalytic inhibition and coupling with TDP1. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PL05-04.