title: Influence of the HER receptor ligand system on sensitivity to cetuximab and trastuzumab in gastric cancer cell lines.
abstract: OBJECTIVE
  Gastric cancer remains a major health concern, and improvement of the therapeutic options is crucial. Treatment with targeted therapeutics such as the EGFR-targeting antibody cetuximab or the HER2-targeting antibody trastuzumab is either ineffective or moderately effective in this disease, respectively. In this study, we analysed the involvement of the HER receptor ligands amphiregulin (AREG), epidermal growth factor (EGF), heparin-binding epidermal growth factor (HB-EGF) and transforming growth factor alpha (TGFα) in the responsiveness of gastric cancer cell lines to cetuximab and trastuzumab.
  
  
  METHODS
  A panel of 11 gastric cancer cell lines was characterized for cetuximab and trastuzumab sensitivity, ligand secretion and expression and activation of the HER receptors using WST-1 cell proliferation assays, ELISAs and Western blot analyses. We further investigated the effects of an exogenous ligand application on the cetuximab and trastuzumab sensitivity.
  
  
  RESULTS
  We found no correlation between TGFα secretion and the sensitivity to cetuximab or trastuzumab. For AREG, we confirmed previous results indicating that this ligand is a positive predictor of cetuximab sensitivity. Exogenous HB-EGF was effective in rescuing sensitive cell lines from inhibition of cell proliferation by both, cetuximab and trastuzumab.
  
  
  CONCLUSIONS
  Our data indicate that HB-EGF may be a useful marker for the prediction of trastuzumab sensitivity in gastric cancer.
authors.affiliation: Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Kneissl
authors.affiliation: Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Hartmann
authors.affiliation: Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Pfarr
authors.affiliation: Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Erlmeier
authors.affiliation: Institute for Pathology, University Hospital Basel, Schönbeinstrasse 40, 4031, Basel, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lorber
authors.affiliation: Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Keller
authors.affiliation: Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany.
authors.forename: Gwen
authors.initials: G
authors.lastname: Zwingenberger
authors.affiliation: Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany.
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
authors.affiliation: Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany. birgit.luber@tum.de.
authors.forename: Birgit
authors.identifier: http://orcid.org/0000-0002-6900-0944
authors.initials: B
authors.lastname: Luber
mesh_terms: D066258:Amphiregulin / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000627:therapeutic use*; D004815:Epidermal Growth Factor / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor / Q000378:metabolism; D006801:Humans; D008024:Ligands; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D000068878:Trastuzumab / Q000627:therapeutic use*
chemical_list: D066258:Amphiregulin; D000970:Antineoplastic Agents; D000068818:Cetuximab; D004815:Epidermal Growth Factor; D066257:Heparin-binding EGF-like Growth Factor; D008024:Ligands; D018719:Erb-b2 Receptor Tyrosine Kinases; D016211:Transforming Growth Factor alpha; D000068878:Trastuzumab
keywords: Cetuximab; EGFR; Gastric cancer; HER receptors; Ligand; Trastuzumab