Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin)

J Natl Cancer Inst. 2001 Dec 19;93(24):1852-7. doi: 10.1093/jnci/93.24.1852.


Background: Trastuzumab (Herceptin), an anti-HER2/neu receptor monoclonal antibody that inhibits growth of ErbB2-overexpressing breast cancer, is used to treat such cancers. Development of resistance to trastuzumab, however, is common. We investigated whether insulin-like growth factor-I (IGF-I), which activates cell survival signals, interferes with the growth-inhibitory action of trastuzumab.

Methods: MCF-7/HER2-18 and SKBR3 human breast cancer models were used to assess cell proliferation, colony formation in soft agar, and cell cycle parameters. Throughout, we used trastuzumab at a dose of 10 microg/mL and IGF-I at a dose of 40 ng/mL. All statistical tests were two-sided.

Results: Trastuzumab inhibited the growth of MCF-7/HER2-18 cells, which overexpress HER2/neu receptors and express IGF-I receptors (IGF-IRs), only when IGF-IR signaling was minimized. For example, in 1% fetal bovine serum (FBS), trastuzumab reduced cell proliferation by 42% (P =.002); however, in 10% FBS or IGF-I, trastuzumab had no effect on proliferation. In SKBR3 cells, which overexpress HER2/neu receptor but express few IGF-IRs, trastuzumab reduced proliferation by 42% (P =.008) regardless of IGF-I concentration. When SKBR3 cells were genetically altered to overexpress IGF-IRs and cultured with IGF-I, trastuzumab had no effect on proliferation. However, the addition of IGF-binding protein-3, which decreased IGF-IR signaling, restored trastuzumab-induced growth inhibition.

Conclusions: In breast cancer cell models that overexpress HER2/neu, an increased level of IGF-IR signaling appears to interfere with the action of trastuzumab. Thus, strategies that target IGF-IR signaling may prevent or delay development of resistance to trastuzumab.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents / pharmacology*
  • Blotting, Western
  • Breast Neoplasms / drug therapy
  • Cell Division
  • Cell Survival
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm*
  • Flow Cytometry
  • G1 Phase / drug effects
  • Humans
  • Insulin-Like Growth Factor Binding Protein 3 / pharmacology
  • Insulin-Like Growth Factor I / pharmacology
  • Precipitin Tests
  • Receptor, ErbB-2 / metabolism
  • Receptor, IGF Type 1 / metabolism*
  • Signal Transduction*
  • Transfection
  • Trastuzumab
  • Tumor Cells, Cultured


  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • Insulin-Like Growth Factor Binding Protein 3
  • Insulin-Like Growth Factor I
  • Receptor, ErbB-2
  • Receptor, IGF Type 1
  • Trastuzumab