Tumor-selective use of DNA base excision repair inhibition in pancreatic cancer using the NQO1 bioactivatable drug, β-lapachone

• Published in: Scientific reports Vol. 5; no. 1; p. 17066
• Main Authors: Chakrabarti, Gaurab, Silvers, Molly A., Ilcheva, Mariya, Liu, Yuliang, Moore, Zachary R., Luo, Xiuquan, Gao, Jinming, Anderson, Glenda, Liu, Lili, Sarode, Venetia, Gerber, David E., Burma, Sandeep, DeBerardinis, Ralph J., Gerson, Stanton L., Boothman, David A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.11.2015; Nature Publishing Group
• Subjects: 13; 13/106; 13/89; 14/19; 59; 631/67/1059/602; 631/67/1504/1713; 64/60; Animals; Autophagy - drug effects; Catalase - genetics; Catalase - metabolism; Cell Line, Tumor; Cell Survival - drug effects; Dicumarol - pharmacology; DNA Breaks, Double-Stranded - drug effects; DNA Glycosylases - antagonists & inhibitors; DNA Glycosylases - metabolism; DNA Repair - drug effects; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - metabolism; Female; Humanities and Social Sciences; Humans; Hydroxylamines - pharmacology; Hydroxylamines - therapeutic use; Mice; Mice, Nude; multidisciplinary; NAD(P)H Dehydrogenase (Quinone) - antagonists & inhibitors; NAD(P)H Dehydrogenase (Quinone) - metabolism; Naphthoquinones - pharmacology; Naphthoquinones - therapeutic use; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Poly(ADP-ribose) Polymerases - metabolism; Reactive Oxygen Species - metabolism; Science; Transplantation, Heterologous; X-ray Repair Cross Complementing Protein 1
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep17066

Base excision repair (BER) is an essential pathway for pancreatic ductal adenocarcinoma (PDA) survival. Attempts to target this repair pathway have failed due to lack of tumor-selectivity and very limited efficacy. The NAD(P)H:Quinone Oxidoreductase 1 (NQO1) bioactivatable drug, ß-lapachone (ARQ761 in clinical form), can provide tumor-selective and enhanced synergy with BER inhibition. ß-Lapachone undergoes NQO1-dependent futile redox cycling, generating massive intracellular hydrogen peroxide levels and oxidative DNA lesions that stimulate poly(ADP-ribose) polymerase 1 (PARP1) hyperactivation. Rapid NAD + /ATP depletion and programmed necrosis results. To identify BER modulators essential for repair of ß-lapachone-induced DNA base damage, a focused synthetic lethal RNAi screen demonstrated that silencing the BER scaffolding protein, XRCC1, sensitized PDA cells. In contrast, depleting OGG1 N-glycosylase spared cells from ß-lap-induced lethality and blunted PARP1 hyperactivation. Combining ß-lapachone with XRCC1 knockdown or methoxyamine (MeOX), an apyrimidinic/apurinic (AP)-modifying agent, led to NQO1-dependent synergistic killing in PDA, NSCLC, breast and head and neck cancers. OGG1 knockdown, dicoumarol-treatment or NQO1- cancer cells were spared. MeOX + ß-lapachone exposure resulted in elevated DNA double-strand breaks, PARP1 hyperactivation and TUNEL+ programmed necrosis. Combination treatment caused dramatic antitumor activity, enhanced PARP1-hyperactivation in tumor tissue and improved survival of mice bearing MiaPaca2-derived xenografts, with 33% apparent cures. Significance: Targeting base excision repair (BER) alone has limited therapeutic potential for pancreatic or other cancers due to a general lack of tumor-selectivity. Here, we present a treatment strategy that makes BER inhibition tumor-selective and NQO1-dependent for therapy of most solid neoplasms, particularly for pancreatic cancer.