title: Inhibition of IGF1R activity enhances response to trastuzumab in HER-2-positive breast cancer cells.
abstract: BACKGROUND
  although trastuzumab has improved the prognosis for HER-2-positive breast cancer patients, not all HER-2-positive breast tumours respond to trastuzumab treatment and those that initially respond frequently develop resistance. Insulin-like growth factor-1 receptor (IGF1R) signalling has been previously implicated in trastuzumab resistance. We tested IGF1R inhibition to determine if dual targeting of HER-2 and IGF1R improves response in cell line models of acquired trastuzumab resistance.
  
  
  METHODS
  HER-2, IGF1R, phospho-HER-2, and phospho-IGF1R levels were measured by enzyme-linked immunosorbent assays in parental and trastuzumab-resistant SKBR3 and BT474 cells. IGF1R signalling was targeted in these cells using both small interfering RNA (siRNA) and the tyrosine kinase inhibitor, NVP-AEW541.
  
  
  RESULTS
  IGF1R levels were significantly increased in the trastuzumab-resistant model, SKBR3/Tr, compared with the parental SKBR3 cell line. In both the SKBR3/Tr and BT474/Tr cell lines, inhibition of IGF1R expression with siRNA or inhibition of tyrosine kinase activity by NVP-AEW541 significantly increased response to trastuzumab. The dual targeting approach also improved response in the parental SKBR3 cells but not in the BT474 parental cells.
  
  
  CONCLUSIONS
  our results confirm that IGF1R inhibition improves response to trastuzumab in HER-2-positive breast cancer cells and suggest that dual targeting of IGF1R and HER-2 may improve response in HER-2-positive tumours.
authors.affiliation: National Institute for Cellular Biotechnology, Dublin City University, Dublin 9.
authors.forename: B C
authors.initials: BC
authors.lastname: Browne
authors.affiliation: National Institute for Cellular Biotechnology, Dublin City University, Dublin 9; Department of Medical Oncology, St. Vincent's University Hospital, Dublin 4, Ireland.
authors.forename: J
authors.initials: J
authors.lastname: Crown
authors.affiliation: Division of Hematology and Oncology, University of California, Los Angeles, CA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Venkatesan
authors.affiliation: Department of Pathology and Laboratory Medicine, St Vincent's University Hospital, and UCD School of Medicine and Medical Science, Conway Institute, University College Dublin, Dublin 4, Ireland.
authors.forename: M J
authors.initials: MJ
authors.lastname: Duffy
authors.affiliation: National Institute for Cellular Biotechnology, Dublin City University, Dublin 9.
authors.forename: M
authors.initials: M
authors.lastname: Clynes
authors.affiliation: Division of Hematology and Oncology, University of California, Los Angeles, CA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Slamon
authors.affiliation: National Institute for Cellular Biotechnology, Dublin City University, Dublin 9. Electronic address: norma.odonovan@dcu.ie.
authors.forename: N
authors.initials: N
authors.lastname: O'Donovan
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000628:therapy*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D011758:Pyrroles / Q000008:administration & dosage; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D017526:Receptor, IGF Type 1; D000068878:Trastuzumab; C501177:NVP-AEW541