title: Acquisition of Relative Interstrand Crosslinker Resistance and PARP Inhibitor Sensitivity in Fanconi Anemia Head and Neck Cancers.
abstract: OBJECTIVE
  Fanconi anemia is an inherited disorder associated with a constitutional defect in the Fanconi anemia DNA repair machinery that is essential for resolution of DNA interstrand crosslinks. Individuals with Fanconi anemia are predisposed to formation of head and neck squamous cell carcinomas (HNSCC) at a young age. Prognosis is poor, partly due to patient intolerance of chemotherapy and radiation requiring dose reduction, which may lead to early recurrence of disease.
  
  
  METHODS
  Using HNSCC cell lines derived from the tumors of patients with Fanconi anemia, and murine HNSCC cell lines derived from the tumors of wild-type and Fancc(-/-) mice, we sought to define Fanconi anemia-dependent chemosensitivity and DNA repair characteristics. We utilized DNA repair reporter assays to explore the preference of Fanconi anemia HNSCC cells for non-homologous end joining (NHEJ).
  
  
  RESULTS
  Surprisingly, interstrand crosslinker (ICL) sensitivity was not necessarily Fanconi anemia-dependent in human or murine cell systems. Our results suggest that the increased Ku-dependent NHEJ that is expected in Fanconi anemia cells did not mediate relative ICL resistance. ICL exposure resulted in increased DNA damage sensing and repair by PARP in Fanconi anemia-deficient cells. Moreover, human and murine Fanconi anemia HNSCC cells were sensitive to PARP inhibition, and sensitivity of human cells was attenuated by Fanconi anemia gene complementation.
  
  
  CONCLUSIONS
  The observed reliance upon PARP-mediated mechanisms reveals a means by which Fanconi anemia HNSCCs can acquire relative resistance to the ICL-based chemotherapy that is a foundation of HNSCC treatment, as well as a potential target for overcoming chemoresistance in the chemosensitive individual.
authors.affiliation: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Lombardi
authors.affiliation: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Hoskins
authors.affiliation: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Grant D
authors.initials: GD
authors.lastname: Foglesong
authors.affiliation: Pathology and Laboratory Medicine and Pulmonary Biology, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio.
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Wikenheiser-Brokamp
authors.affiliation: Department of Obstetrics and Gynaecology, University of Ulm, Ulm, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Wiesmüller
authors.affiliation: Department of Pediatrics and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana. Department of Otorhinolaryngology (ENT/HNO), Heinrich Heine University School of Medicine, Duesseldorf, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Hanenberg
authors.affiliation: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Andreassen
authors.affiliation: Department of Hematology/Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, Oregon. Portland VA Medical Center, Portland, Oregon.
authors.forename: Allison J
authors.initials: AJ
authors.lastname: Jacobs
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon.
authors.forename: Susan B
authors.initials: SB
authors.lastname: Olson
authors.affiliation: Department of Hematology/Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, Oregon. Portland VA Medical Center, Portland, Oregon.
authors.forename: Winifred W
authors.initials: WW
authors.lastname: Keeble
authors.affiliation: Department of Hematology/Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, Oregon. Portland VA Medical Center, Portland, Oregon. susanne.wells@cchmc.org laura@fanconi.org.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Hays
authors.affiliation: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. susanne.wells@cchmc.org laura@fanconi.org.
authors.forename: Susanne I
authors.initials: SI
authors.lastname: Wells
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects; D059766:DNA End-Joining Repair; D004265:DNA Helicases / Q000378:metabolism; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004789:Enzyme Activation; D005199:Fanconi Anemia / Q000150:complications* / Q000235:genetics*; D052218:Fanconi Anemia Complementation Group C Protein / Q000235:genetics; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000172:deficiency / Q000378:metabolism; D055786:Gene Knockout Techniques; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000209:etiology*; D064593:Heterografts; D006801:Humans; D000072200:Ku Autoantigen; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D018874:Spheroids, Cellular; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D052218:Fanconi Anemia Complementation Group C Protein; D052236:Fanconi Anemia Complementation Group D2 Protein; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D004265:DNA Helicases; C106893:XRCC5 protein, human; D000072200:Ku Autoantigen; D002945:Cisplatin