title: Tumor-selective use of DNA base excision repair inhibition in pancreatic cancer using the NQO1 bioactivatable drug, β-lapachone.
abstract: 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
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Departments of Pharmacology, Dallas, TX 75390-8807.|Radiation Oncology, Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390-8807.
authors.forename: Gaurab
authors.initials: G
authors.lastname: Chakrabarti
authors.affiliation: Departments of Pharmacology, Dallas, TX 75390-8807.|Radiation Oncology, Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390-8807.
authors.forename: Molly A
authors.initials: MA
authors.lastname: Silvers
authors.affiliation: Radiation Oncology, Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390-8807.
authors.forename: Mariya
authors.initials: M
authors.lastname: Ilcheva
authors.affiliation: Departments of Pharmacology, Dallas, TX 75390-8807.|Radiation Oncology, Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390-8807.
authors.forename: Yuliang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Departments of Pharmacology, Dallas, TX 75390-8807.|Radiation Oncology, Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390-8807.
authors.forename: Zachary R
authors.initials: ZR
authors.lastname: Moore
authors.affiliation: Departments of Pharmacology, Dallas, TX 75390-8807.|Radiation Oncology, Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390-8807.
authors.forename: Xiuquan
authors.initials: X
authors.lastname: Luo
authors.affiliation: Departments of Pharmacology, Dallas, TX 75390-8807.
authors.forename: Jinming
authors.initials: J
authors.lastname: Gao
authors.affiliation: 5 Degrees Bio, San Jose, CA 95113.
authors.forename: Glenda
authors.initials: G
authors.lastname: Anderson
authors.affiliation: Department of Hematology and Oncology, Case Western Reserve Comprehensive Cancer Center, Cleveland, OH 44106.
authors.forename: Lili
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390-9234.
authors.forename: Venetia
authors.initials: V
authors.lastname: Sarode
authors.affiliation: Radiation Oncology, Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390-8807.
authors.forename: David E
authors.initials: DE
authors.lastname: Gerber
authors.affiliation: Radiation Oncology, Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390-8807.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Burma
authors.affiliation: Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, TX 75390-8502.
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: DeBerardinis
authors.affiliation: Department of Hematology and Oncology, Case Western Reserve Comprehensive Cancer Center, Cleveland, OH 44106.
authors.forename: Stanton L
authors.initials: SL
authors.lastname: Gerson
authors.affiliation: Departments of Pharmacology, Dallas, TX 75390-8807.|Radiation Oncology, Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390-8807.
authors.forename: David A
authors.initials: DA
authors.lastname: Boothman
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D045647:DNA Glycosylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D001728:Dicumarol / Q000494:pharmacology; D005260:Female; D006801:Humans; D006898:Hydroxylamines / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009285:Naphthoquinones / Q000494:pharmacology / Q000627:therapeutic use; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014183:Transplantation, Heterologous; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: D004268:DNA-Binding Proteins; D006898:Hydroxylamines; D009285:Naphthoquinones; D017382:Reactive Oxygen Species; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; C000619352:Xrcc1 protein, mouse; C014638:beta-lapachone; D001728:Dicumarol; C005214:methoxyamine; D002374:Catalase; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D011065:Poly(ADP-ribose) Polymerases; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human