Inhibition of IGF1R activity enhances response to trastuzumab in HER-2-positive breast cancer cells

Ann Oncol. 2011 Jan;22(1):68-73. doi: 10.1093/annonc/mdq349. Epub 2010 Jul 20.


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.

Materials and 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / administration & dosage
  • Antibodies, Monoclonal / therapeutic use*
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / therapy*
  • Cell Growth Processes / drug effects
  • Cell Line, Tumor
  • Combined Modality Therapy
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Female
  • Humans
  • Protein Kinase Inhibitors / administration & dosage
  • Pyrimidines / administration & dosage
  • Pyrroles / administration & dosage
  • RNA, Small Interfering / administration & dosage
  • RNA, Small Interfering / genetics
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Receptor, ErbB-2 / biosynthesis
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism
  • Receptor, IGF Type 1 / antagonists & inhibitors*
  • Receptor, IGF Type 1 / genetics
  • Receptor, IGF Type 1 / metabolism
  • Transfection
  • Trastuzumab


  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • NVP-AEW541
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Pyrroles
  • RNA, Small Interfering
  • Receptor, ErbB-2
  • Receptor, IGF Type 1
  • Trastuzumab