Abstract 2734: Veliparib (ABT-888) potentiates the cytotoxic activity of DNA alkylating agents by trapping PARP onto damaged chromatin
Authors: Larry Solomon, Todd Hopkins, Yan Shi, Paul Ellis, Cherrie Donawho, Eric F. Johnson, Guowei Fang, David Maag
Journal: Cancer Research (2014)

Abstract PARP-1 and PARP-2 are required for base excision repair (BER) and also function to regulate homologous recombination and non-homologous end joining. Inhibitors of these enzymes have demonstrated context-dependent anti-tumor activity, particularly in combination with DNA damaging agents and in tumors with DNA repair deficits. For this reason, there is considerable interest in the ongoing clinical development of PARP inhibitors as anti-cancer therapies. However, due to the diversity and complexity of PARP function in DNA repair, the mechanisms of action of PARP inhibitors have not been fully characterized. Recent reports have suggested that one mechanism whereby PARP inhibitors potentiate cytotoxicity of DNA alkylating agents is via trapping of PARP at sites of DNA damage during BER, generating bulky PARP-DNA lesions that prevent subsequent steps in the BER process and ultimately lead to cytotoxic double-strand breaks. Two non-mutually exclusive models have been proposed to explain this effect. In the first, PARP inhibition prevents auto-PARylation, which is known to promote dissociation of PARP from DNA. In the second, PARP inhibitors allosterically enhance the affinity of PARP for damaged DNA in a manner not predicted by catalytic potency. In support of this model, it has been reported that the PARP inhibitors veliparib and olaparib differ significantly in ability to induce trapping while having similar catalytic potency. Contrary to this hypothesis, both compounds robustly potentiate the activity of alkylating agents in vitro and in vivo, achieving similar efficacy when combined with temozolomide in xenograft studies. In this study, we used a combination of biochemical and cellular techniques to characterize the ability of veliparib to trap PARP onto damaged DNA at pharmacologically relevant concentrations. A comparison of veliparib to other PARP inhibitors revealed a strong correlation in potency with respect to catalytic inhibition, trapping and potentiation of DNA alkylating agents. Furthermore, kinetic and equilibrium binding analysis of PARP DNA binding activity revealed no evidence of allostery with any of the PARP inhibitors examined. Collectively, these observations favor the auto-PARylation model and provide no justification to invoke an allosteric mechanism. Consequently, there is no premise for PARP inhibitor differentiation based on catalytic versus trapping potency. Moreover, it is noteworthy that we have thus far been unable to observe trapping with other classes of DNA damaging agents, suggesting that this mechanism may not translate to other combination regimens currently being evaluated in the clinic. Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. Citation Format: Larry Solomon, Todd Hopkins, Yan Shi, Paul Ellis, Cherrie Donawho, Eric F. Johnson, Guowei Fang, David Maag. Veliparib (ABT-888) potentiates the cytotoxic activity of DNA alkylating agents by trapping PARP onto damaged chromatin. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2734. doi:10.1158/1538-7445.AM2014-2734