title: Dual disruption of DNA repair and telomere maintenance for the treatment of head and neck cancer.
abstract: OBJECTIVE
  Poly(ADP-ribose) polymerases (PARP) and the Mre11, Rad50, and Nbs1 (MRN) complex are key regulators of DNA repair, and have been recently shown to independently regulate telomere length. Sensitivity of cancers to PARPi is largely dependent on the BRCAness of the cells. Unfortunately, the vast majority of cancers are BRCA-proficient. In this study, therefore, we investigated whether a targeted molecular "hit" on the MRN complex, which is upstream of BRCA, can effectively sensitize BRCA-proficient head and neck squamous cell carcinoma (HNSCC) to PARP inhibitor (PARPi).
  
  
  METHODS
  Human HNSCC cell lines and a mouse model with HNSCC xenografts were used in this study. In vitro and in vivo studies were conducted to evaluate the effects and underlying mechanisms of dual molecular disruption of PARP and the MRN complex, using a pharmacologic inhibitor and a dominant-negative Nbs1 expression vector, respectively.
  
  
  RESULTS
  Our findings demonstrate that downregulation of the MRN complex disrupts homologous recombination, and, when combined with PARPi, leads to accumulation of lethal DNA double-strand breaks. Moreover, we show that PARPi and MRN complex disruption induces significantly shortening telomere length. Together, our results demonstrate that dual disruption of these pathways causes significant cell death in BRCA-proficient tumor cells both in vitro and in vivo.
  
  
  CONCLUSIONS
  Our study, for the first time, elucidates a novel mechanism for MRN complex and PARP inhibition beyond DNA repair, demonstrating the feasibility of a dual disruption approach that extends the utility of PARPi to the treatment of BRCA-proficient cancers.
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Shayanne A
authors.initials: SA
authors.lastname: Lajud
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Danish A
authors.initials: DA
authors.lastname: Nagda
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania. Department of Otolaryngology-Head and Neck Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Jun
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania. Department of Otolaryngology-Head and Neck Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Tanaka
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania. Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, California.
authors.forename: Waleed M
authors.initials: WM
authors.lastname: Abuzeid
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Alyssa
authors.initials: A
authors.lastname: Civantos
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Orysia
authors.initials: O
authors.lastname: Bezpalko
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Bert W
authors.initials: BW
authors.lastname: O'Malley
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania. lidaqing@mail.med.upenn.edu.
authors.forename: Daqing
authors.initials: D
authors.lastname: Li
mesh_terms: D017766:Acid Anhydride Hydrolases; D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D053904:DNA Breaks, Single-Stranded / Q000187:drug effects; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D042822:Genomic Instability; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D006801:Humans; D000076228:MRE11 Homologue Protein; D051379:Mice; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D009930:Organic Chemicals / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D000077195:Squamous Cell Carcinoma of Head and Neck; D016615:Telomere / Q000235:genetics* / Q000378:metabolism*; D059506:Telomere Shortening; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D019313:BRCA1 Protein; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; D046912:Multiprotein Complexes; C112156:NBN protein, human; D009687:Nuclear Proteins; D009930:Organic Chemicals; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C502278:GPI 15427; D011065:Poly(ADP-ribose) Polymerases; D000076228:MRE11 Homologue Protein; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes