title: Poly (ADP-ribose) polymerase inhibition enhances trastuzumab antitumour activity in HER2 overexpressing breast cancer.
abstract: OBJECTIVE
  Poly (ADP-ribose) polymerase (PARP) inhibitors have shown promising results in Breast Cancer (BRCA) deficient breast cancer, but not in molecularly unselected patient populations. Two lines of research in this field are needed: the identification of novel subsets of patients that could potentially benefit from PARP inhibitors and the discovery of suitable targeted therapies for combination strategies.
  
  
  METHODS
  We tested PARP inhibition, alone or combined with the anti-HER2 antibody trastuzumab on HER2+ breast cancer. We used two PARP inhibitors in clinical development, olaparib and rucaparib, as well as genetic downmodulation of PARP-1 for in vitro studies. DNA damage was studied by the formation of γH2AX foci and comet assay. Finally, the in vivo anti-tumour effect of olaparib and trastuzumab was examined in nude mice subcutaneously implanted with BT474 cells.
  
  
  RESULTS
  In a panel of four HER2 overexpressing breast cancer cell lines, both olaparib and rucaparib significantly decreased cell growth and enhanced anti-tumour effects of trastuzumab. Cells exposed to olaparib and trastuzumab had greater DNA damage than cells exposed to each agent alone. Mechanistic exploratory assays showed that trastuzumab downmodulated the homologous recombination protein proliferating cell nuclear antigen (PCNA). Combination treatment in the BT474 xenograft model resulted in enhanced growth inhibition, reduced tumour cell proliferation, and increased DNA damage and apoptosis.
  
  
  CONCLUSIONS
  Taken together, our results show that PARP inhibition has antitumour effects and increases trastuzumab activity in HER2 overexpressing breast cancer. These findings make this novel combination a promising strategy for clinical development.
authors.affiliation: Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain; Medical Oncology Department, Hospital del Mar, Barcelona, Spain.
authors.forename: Jetzabel
authors.initials: J
authors.lastname: García-Parra
authors.affiliation: Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain; Medical Oncology Department, Hospital del Mar, Barcelona, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Dalmases
authors.affiliation: Preclinical Research Program, Valld'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Morancho
authors.affiliation: Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain; Medical Oncology Department, Hospital del Mar, Barcelona, Spain.
authors.forename: Oriol
authors.initials: O
authors.lastname: Arpí
authors.affiliation: Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain; Medical Oncology Department, Hospital del Mar, Barcelona, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Menendez
authors.affiliation: Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain; Medical Oncology Department, Hospital del Mar, Barcelona, Spain.
authors.forename: MohammadA
authors.initials: M
authors.lastname: Sabbaghi
authors.affiliation: Pathology Department, IIS-Fundación Jiménez Díaz, Madrid, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Zazo
authors.affiliation: Pathology Department, IIS-Fundación Jiménez Díaz, Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Chamizo
authors.affiliation: Pathology Department, IIS-Fundación Jiménez Díaz, Madrid, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Madoz
authors.affiliation: Institute of Health Research INCLIVA, Valencia, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Eroles
authors.affiliation: Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain; Medical Oncology Department, Hospital del Mar, Barcelona, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Servitja
authors.affiliation: Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain; Medical Oncology Department, Hospital del Mar, Barcelona, Spain; Autonomous University of Barcelona, Spain.
authors.forename: Ignasi
authors.initials: I
authors.lastname: Tusquets
authors.affiliation: Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain; Immunology Department, Hospital del Mar, Barcelona, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: Yelamos
authors.affiliation: Oncology and Hematology Department, Hospital Clinico Universitario, Valencia, Spain; Valencia Central University, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Lluch
authors.affiliation: Preclinical Research Program, Valld'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Bellaterra, Spain; Institució Catalana de Recerca I Estudis Avançats (ICREA), Barcelona, Spain.
authors.forename: Joaquin
authors.initials: J
authors.lastname: Arribas
authors.affiliation: Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain; Pathology Department, IIS-Fundación Jiménez Díaz, Madrid, Spain; Pathology Department, Hospital del Mar, Barcelona, Spain.
authors.forename: Federico
authors.initials: F
authors.lastname: Rojo
authors.affiliation: Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain; Medical Oncology Department, Hospital del Mar, Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Rovira
authors.affiliation: Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain; Medical Oncology Department, Hospital del Mar, Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain. Electronic address: jalbanell@hospitaldelmar.cat.
authors.forename: Joan
authors.initials: J
authors.lastname: Albanell
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010793:Phthalazines / Q000008:administration & dosage / Q000494:pharmacology; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068878:Trastuzumab; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D006657:Histones; D007211:Indoles; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D018809:Proliferating Cell Nuclear Antigen; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C468783:H2AX protein, human; C531549:rucaparib; C531550:olaparib
keywords: Breast cancer; HER2; Olaparib; PARP; Rucaparib; Trastuzumab