Targeting ERBB receptors shifts their partners and triggers persistent ERK signaling through a novel ERBB/EFNB1 complex

Cancer Res. 2013 Sep 15;73(18):5787-97. doi: 10.1158/0008-5472.CAN-13-0760. Epub 2013 Jun 28.

Abstract

Most squamous cell carcinomas of the head and neck (HNSCC) overexpress ERBB1/EGFR, but EGF receptor (EGFR)-targeted therapies have yielded disappointing clinical results in treatment of this cancer. Here, we describe a novel interaction between EGFR and the ligand EphrinB1 (EFNB1), and we show that EFNB1 phosphorylation and downstream signaling persists in the presence of cetuximab. Mechanistically, cetuximab drives a shift in EGFR dimerization partners within the signaling complex, suggesting that targeted drugs may trigger partner rearrangements that allow persistent pathway activation. EFNB1 attenuation slowed tumor growth and increased survival in a murine model of HNSCC, suggesting a substantial contribution of EFNB1 signaling to HNSCC development. Together, our findings suggest that EFNB1 is part of the EGFR signaling complex and may mediate drug resistance in HNSCC as well as other solid tumors.

Publication types

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

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / pharmacology*
  • Antineoplastic Agents / pharmacology
  • Blotting, Western
  • Carcinoma, Squamous Cell / drug therapy
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Cetuximab
  • Drug Resistance, Neoplasm
  • Ephrin-B1 / antagonists & inhibitors
  • Ephrin-B1 / metabolism*
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism*
  • Fluorescent Antibody Technique
  • Head and Neck Neoplasms / drug therapy*
  • Head and Neck Neoplasms / metabolism
  • Head and Neck Neoplasms / pathology
  • Humans
  • Immunoprecipitation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Phosphorylation / drug effects
  • Protein Multimerization / drug effects
  • Protein Tyrosine Phosphatase, Non-Receptor Type 13 / antagonists & inhibitors
  • Protein Tyrosine Phosphatase, Non-Receptor Type 13 / metabolism
  • Receptor, ErbB-2 / antagonists & inhibitors
  • Receptor, ErbB-2 / metabolism*
  • Signal Transduction / drug effects

Substances

  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • EFNB1 protein, human
  • Ephrin-B1
  • ERBB2 protein, human
  • ErbB Receptors
  • Receptor, ErbB-2
  • MAPK1 protein, human
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • PTPN13 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 13
  • Cetuximab