Abstract 2743: Triapine sensitizes ovarian cancer cells to platinum drugs and PARP inhibitors

Abstract

Abstract Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone) is a ribonucleotide reductase (RNR) inhibitor that is 1000-times more potent than clinically-used hydroxyurea. Consisting primarily of R2 and R1 subunits during the S phase of the cell cycle, RNR catalyzes the rate-limiting step in the production of deoxyribonucleotides (dNTPs) required for DNA synthesis. Triapine chelates iron to form the triapine-Fe complex that quenches the tyrosyl radical at the R2 subunit and leads to enzymatic inactivation. In recent phase I and II trials, treatment of locally advanced cervical cancer with triapine in combination with cisplatin and radiation was well tolerated and produced high durable complete clinical responses in patients. This promising combination therapy may be attributable to the inhibitory effects of triapine on the repair of cisplatin- and radiation-induced DNA damage. However, the exact DNA repair mechanisms modulated by triapine remain poorly understood. In this study, we demonstrate that treatment of ovarian cancer cells with triapine prompts rapid and prolonged depletion of dATP/dNTP pools, which in turn leads to formation of DNA double strand breaks (DSBs) and inhibition of DNA synthesis in S and G2/M phases of the cell cycle. Furthermore, we show that treatment with triapine results in enhanced sensitization of BRCA-proficient (wild-type) ovarian cancer cells to platinum drugs (cisplatin and carboplatin) and the PARP inhibitor olaparib. Both platinum drugs and PARP inhibitors indirectly cause DSBs which require BRCA1- and BRCA2-dependent homologous recombination (HR) to repair. Collectively, these results suggest that triapine acts to abrogate replicative DNA synthesis and post-replication repair, thereby deterring HR repair of DSBs caused by platinum drugs and other DNA damaging modalities. While 70% of ovarian cancer patients initially respond to platinum-based chemotherapy, the majority of these patients will develop recurrent cancer resistant to the platinum drugs. Emergence of platinum-resistant cancer populations may be associated with increasing proficiency of cancer cells to employ HR to repair DNA damage. Given that, our findings provide the rationale for the use of triapine to enhance the efficacy of platinum-based chemotherapy and PARP inhibitors, and potentially eradicate platinum-resistant ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2743. doi:1538-7445.AM2012-2743