title: Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors.
abstract: Therapeutic drugs that block DNA repair, including poly(ADP-ribose) polymerase (PARP) inhibitors, fail due to lack of tumor-selectivity. When PARP inhibitors and β-lapachone are combined, synergistic antitumor activity results from sustained NAD(P)H levels that refuel NQO1-dependent futile redox drug recycling. Significant oxygen-consumption-rate/reactive oxygen species cause dramatic DNA lesion increases that are not repaired due to PARP inhibition. In NQO1+cancers, such as non-small-cell lung, pancreatic, and breast cancers, cell death mechanism switches from PARP1 hyperactivation-mediated programmed necrosis with β-lapachone monotherapy to synergistic tumor-selective, caspase-dependent apoptosis with PARP inhibitors and β-lapachone. Synergistic antitumor efficacy and prolonged survival were noted in human orthotopic pancreatic and non-small-cell lung xenograft models, expanding use and efficacy of PARP inhibitors for human cancer therapy.
authors.affiliation: Departments of Pharmacology and Radiation Oncology, Simmons Comprehensive Cancer Center (SCCC), UT Southwestern Medical Center (UTSW), Dallas, TX 75390, USA.
authors.forename: Xiumei
authors.initials: X
authors.lastname: Huang
authors.affiliation: Departments of Pharmacology and Radiation Oncology, Simmons Comprehensive Cancer Center (SCCC), UT Southwestern Medical Center (UTSW), Dallas, TX 75390, USA.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Motea
authors.affiliation: Departments of Pharmacology and Radiation Oncology, Simmons Comprehensive Cancer Center (SCCC), UT Southwestern Medical Center (UTSW), Dallas, TX 75390, USA.
authors.forename: Zachary R
authors.initials: ZR
authors.lastname: Moore
authors.affiliation: Departments of Pharmacology and Radiation Oncology, Simmons Comprehensive Cancer Center (SCCC), UT Southwestern Medical Center (UTSW), Dallas, TX 75390, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Yao
authors.affiliation: Departments of Pharmacology and Radiation Oncology, Simmons Comprehensive Cancer Center (SCCC), UT Southwestern Medical Center (UTSW), Dallas, TX 75390, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Departments of Pharmacology and Radiation Oncology, Simmons Comprehensive Cancer Center (SCCC), UT Southwestern Medical Center (UTSW), Dallas, TX 75390, USA.
authors.forename: Gaurab
authors.initials: G
authors.lastname: Chakrabarti
authors.affiliation: Department of Biochemistry, SCCC, UTSW, Dallas, TX 75390, USA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Kilgore
authors.affiliation: Departments of Pharmacology and Radiation Oncology, Simmons Comprehensive Cancer Center (SCCC), UT Southwestern Medical Center (UTSW), Dallas, TX 75390, USA.
authors.forename: Molly A
authors.initials: MA
authors.lastname: Silvers
authors.affiliation: Departments of Pharmacology and Radiation Oncology, Simmons Comprehensive Cancer Center (SCCC), UT Southwestern Medical Center (UTSW), Dallas, TX 75390, USA.
authors.forename: Praveen L
authors.initials: PL
authors.lastname: Patidar
authors.affiliation: Departments of Pharmacology and Radiation Oncology, Simmons Comprehensive Cancer Center (SCCC), UT Southwestern Medical Center (UTSW), Dallas, TX 75390, USA.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Cholka
authors.affiliation: Departments of Pharmacology and Radiation Oncology, Simmons Comprehensive Cancer Center (SCCC), UT Southwestern Medical Center (UTSW), Dallas, TX 75390, USA.
authors.forename: Farjana
authors.initials: F
authors.lastname: Fattah
authors.affiliation: Immuneering Corporation, One Broadway 14th Floor, Cambridge, MA 02142, USA.
authors.forename: Yoonjeong
authors.initials: Y
authors.lastname: Cha
authors.affiliation: 5Degrees Bio., Inc., 111 North Market Street #300, San Jose, CA 95113, USA.
authors.forename: Glenda G
authors.initials: GG
authors.lastname: Anderson
authors.affiliation: Immuneering Corporation, One Broadway 14th Floor, Cambridge, MA 02142, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Kusko
authors.affiliation: Department of Internal Medicine, Division of Hematology-Oncology, UTSW, Dallas, TX 75390, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Peyton
authors.affiliation: Department of Biostatistics, UTSW, Dallas, TX 75390, USA.
authors.forename: Jingsheng
authors.initials: J
authors.lastname: Yan
authors.affiliation: Department of Biostatistics, UTSW, Dallas, TX 75390, USA.
authors.forename: Xian-Jin
authors.initials: XJ
authors.lastname: Xie
authors.affiliation: Department of Pathology, UTSW, Dallas, TX 75390, USA.
authors.forename: Venetia
authors.initials: V
authors.lastname: Sarode
authors.affiliation: Department of Biochemistry, SCCC, UTSW, Dallas, TX 75390, USA.
authors.forename: Noelle S
authors.initials: NS
authors.lastname: Williams
authors.affiliation: Department of Internal Medicine, Division of Hematology-Oncology, UTSW, Dallas, TX 75390, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.affiliation: Department of Internal Medicine, Division of Hematology-Oncology, UTSW, Dallas, TX 75390, USA.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Beg
authors.affiliation: Department of Internal Medicine, Division of Hematology-Oncology, UTSW, Dallas, TX 75390, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Gerber
authors.affiliation: Department of Pharmaceutical Sciences, West Virginia University Cancer Institute, Morgantown, WV 26506, USA. Electronic address: erik.bey@hsc.wvu.edu.
authors.forename: Erik A
authors.initials: EA
authors.lastname: Bey
authors.affiliation: Departments of Pharmacology and Radiation Oncology, Simmons Comprehensive Cancer Center (SCCC), UT Southwestern Medical Center (UTSW), Dallas, TX 75390, USA. Electronic address: david.boothman@utsouthwestern.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Boothman
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics*; D009285:Naphthoquinones / Q000008:administration & dosage* / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D009285:Naphthoquinones; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017382:Reactive Oxygen Species; C014638:beta-lapachone; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human
keywords: ARQ761; NQO1; NQO1 bioctivatable drugs; NSCLC; Olaparib; PARP1; PDA; ROS; Rucaparib; combination chemotherapy; synthetic lethality; β-lapachone