title: Poly (ADP-ribose) polymerase inhibitor efficacy in head and neck cancer.
abstract: OBJECTIVE
  Poly (ADP-ribose) polymerase inhibitors (PARPi) have shown single agent activity against tumors with deficiencies in the DNA repair mechanism homologous recombination including, but not limited to those harboring BRCA mutations. We hypothesized that, in the context of homologous recombination deficiency (HRD), PARPi could have an effect in head and neck cancer (HNC).
  
  
  METHODS
  We evaluated TCGA data for evidence of HRD using a copy number data signature established for breast cancer. The comparative potency of three PARPi was evaluated using cell viability assays in a panel of HNC cell lines and response was compared to BRCA-deficient breast cancer cell lines. The change in foci formation of γH2AX and RAD51 was assessed with immunofluorescent staining after exposure to a PARPi. Baseline gene expression was analyzed using microarray data.
  
  
  RESULTS
  We found a subgroup in the TCGA HNC cohort harboring genomic aberrations consistent with HRD in breast cancer. Rucaparib activity was superior to olaparib and veliparib and showed single agent activity in a subset of HNC cell lines that was comparable to BRCA-deficient breast cancer cell lines. Rucaparib-sensitive and rucaparib-resistant groups showed significant differences in γH2AX and RAD51 foci formation after rucaparib exposure. Expression of genes involved in chromosome structure was strongly associated with rucaparib resistance.
  
  
  CONCLUSIONS
  We demonstrate that PARPi are effective in a subset of HNC cell lines and propose that HRD may be present in HNC in vivo suggesting that these compounds could play a role in the treatment of HNC.
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA; Division of Hematology and Oncology, Department of Internal Medicine, Sana City Hospital South, Lübeck, Germany. Electronic address: jana@seiwertlab.com.
authors.forename: Jana
authors.initials: J
authors.lastname: Heitmann
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA. Electronic address: paulgeeleher@gmail.com.
authors.forename: Paul
authors.initials: P
authors.lastname: Geeleher
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA. Electronic address: zhixiang@seiwertlab.com.
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Zuo
authors.affiliation: Department of Radiation Oncology, University of Chicago, Chicago, IL 60637, USA; The University of Chicago Comprehensive Cancer Center, Chicago, IL 60627, USA. Electronic address: rrw@radonc.bsd.uchicago.edu.
authors.forename: Ralph R
authors.initials: RR
authors.lastname: Weichselbaum
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA. Electronic address: evokes@medicine.bsd.uchicago.edu.
authors.forename: Everett E
authors.initials: EE
authors.lastname: Vokes
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, Sana City Hospital South, Lübeck, Germany. Electronic address: s.fetscher@sana-luebeck.de.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Fetscher
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA; The University of Chicago Comprehensive Cancer Center, Chicago, IL 60627, USA. Electronic address: tseiwert@medicine.bsd.uchicago.edu.
authors.forename: Tanguy Y
authors.initials: TY
authors.lastname: Seiwert
mesh_terms: D045744:Cell Line, Tumor; D004249:DNA Damage; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051135:Rad51 Recombinase / Q000235:genetics
chemical_list: D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C495153:RAD51 protein, human; D051135:Rad51 Recombinase
keywords: DNA repair; Head and neck cancer; Homologous recombination; Poly (ADP-ribose) polymerase; Rucaparib