title: Defining the molecular response to trastuzumab, pertuzumab and combination therapy in ovarian cancer.
abstract: BACKGROUND
  Trastuzumab and pertuzumab target the Human Epidermal growth factor Receptor 2 (HER2). Combination therapy has been shown to provide enhanced antitumour activity; however, the downstream signalling to explain how these drugs mediate their response is not clearly understood.
  
  
  METHODS
  Transcriptome profiling was performed after 4 days of trastuzumab, pertuzumab and combination treatment in human ovarian cancer in vivo. Signalling pathways identified were validated and investigated in primary ovarian xenografts at the protein level and across a timeseries.
  
  
  RESULTS
  A greater number and variety of genes were differentially expressed by the combination of antibody therapies compared with either treatment alone. Protein levels of cyclin-dependent kinase inhibitors p21 and p27 were increased in response to both agents and further by the combination; pERK signalling was inhibited by all treatments; but only pertuzumab inhibited pAkt signalling. The expression of proliferation, apoptosis, cell division and cell-cycle markers was distinct in a panel of primary ovarian cancer xenografts, suggesting the heterogeneity of response in ovarian cancer and a need to establish predictive biomarkers.
  
  
  CONCLUSIONS
  This first comprehensive study of the molecular response to trastuzumab, pertuzumab and combined therapy in vivo highlights both common and distinct downstream effects to agents used alone or in combination, suggesting that complementary pathways may be involved.
authors.affiliation: Edinburgh Breakthrough Research Unit, Division of Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK. andrew.sims@ed.ac.uk
authors.forename: A H
authors.initials: AH
authors.lastname: Sims
authors.forename: A J M
authors.initials: AJ
authors.lastname: Zweemer
authors.forename: Y
authors.initials: Y
authors.lastname: Nagumo
authors.forename: D
authors.initials: D
authors.lastname: Faratian
authors.forename: M
authors.initials: M
authors.lastname: Muir
authors.forename: M
authors.initials: M
authors.lastname: Dodds
authors.forename: I
authors.initials: I
authors.lastname: Um
authors.forename: C
authors.initials: C
authors.lastname: Kay
authors.forename: M
authors.initials: M
authors.lastname: Hasmann
authors.forename: D J
authors.initials: DJ
authors.lastname: Harrison
authors.forename: S P
authors.initials: SP
authors.lastname: Langdon
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D015153:Blotting, Western; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C485206:pertuzumab; D000068878:Trastuzumab