Met receptor contributes to trastuzumab resistance of Her2-overexpressing breast cancer cells

Cancer Res. 2008 Mar 1;68(5):1471-7. doi: 10.1158/0008-5472.CAN-07-5962.

Abstract

Her2 is overexpressed in 20% to 30% of breast tumors and correlates with reduced disease-free and overall patient survival. Trastuzumab, a humanized monoclonal antibody directed against Her2, represents the first Her2-targeted therapy, which decreases the risk of relapse and prolongs patient survival. Resistance to trastuzumab, both inherent and treatment-acquired, represents a significant barrier to the effective treatment of Her2 (+) breast cancer. The Met receptor tyrosine kinase is aberrantly expressed in breast cancer and predicts poor patient prognosis. In this study, we find that Met is frequently expressed in Her2-overexpressing breast cancer cells, as well as Her2 (+) breast cancer. Importantly, Met contributes to trastuzumab resistance, as inhibition of Met sensitizes cells to trastuzumab-mediated growth inhibition, whereas Met activation protects cells against trastuzumab by abrogating p27 induction. Remarkably, Her2-overexpressing breast cancer cells rapidly up-regulate Met expression after trastuzumab treatment, promoting their own resistance. Our study suggests that a subset of Her2 (+) patients may benefit from combined inhibition of Her2 and Met.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents / pharmacology
  • Breast / pathology
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Proliferation
  • Drug Resistance, Neoplasm*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Genes, erbB-2*
  • Humans
  • Models, Biological
  • Phosphorylation
  • Proto-Oncogene Proteins c-met / metabolism*
  • Receptor, ErbB-2 / genetics*
  • Receptor, ErbB-2 / physiology*
  • Trastuzumab

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • ERBB2 protein, human
  • Proto-Oncogene Proteins c-met
  • Receptor, ErbB-2
  • Extracellular Signal-Regulated MAP Kinases
  • Trastuzumab