Targeting ADAM-mediated ligand cleavage to inhibit HER3 and EGFR pathways in non-small cell lung cancer

Cancer Cell. 2006 Jul;10(1):39-50. doi: 10.1016/j.ccr.2006.05.024.

Abstract

We describe here the existence of a heregulin-HER3 autocrine loop, and the contribution of heregulin-dependent, HER2-mediated HER3 activation to gefitinib insensitivity in non-small cell lung cancer (NSCLC). ADAM17 protein, a major ErbB ligand sheddase, is upregulated in NSCLC and is required not only for heregulin-dependent HER3 signaling, but also for EGFR ligand-dependent signaling in NSCLC cell lines. A selective ADAM inhibitor, INCB3619, prevents the processing and activation of multiple ErbB ligands, including heregulin. In addition, INCB3619 inhibits gefitinib-resistant HER3 signaling and enhances gefitinib inhibition of EGFR signaling in NSCLC. These results show that ADAM inhibition affects multiple ErbB pathways in NSCLC and thus offers an excellent opportunity for pharmacological intervention, either alone or in combination with other drugs.

Publication types

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

MeSH terms

  • ADAM Proteins / antagonists & inhibitors*
  • ADAM Proteins / genetics
  • ADAM Proteins / metabolism
  • ADAM17 Protein
  • Animals
  • Apoptosis / drug effects
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Cell Line, Tumor
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • Female
  • Gefitinib
  • Gene Expression / genetics
  • Humans
  • Ligands
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Models, Biological
  • Paclitaxel / pharmacology
  • Piperidines / pharmacology*
  • Piperidines / therapeutic use
  • Protease Inhibitors / pharmacology
  • Protease Inhibitors / therapeutic use
  • Protein Kinase Inhibitors / pharmacology
  • Quinazolines / pharmacology
  • Receptor, ErbB-3 / metabolism*
  • Signal Transduction / drug effects*
  • Spiro Compounds / pharmacology*
  • Spiro Compounds / therapeutic use
  • Xenograft Model Antitumor Assays

Substances

  • INCB3619
  • Ligands
  • Piperidines
  • Protease Inhibitors
  • Protein Kinase Inhibitors
  • Quinazolines
  • Spiro Compounds
  • ErbB Receptors
  • Receptor, ErbB-3
  • ADAM Proteins
  • ADAM17 Protein
  • ADAM17 protein, human
  • Adam17 protein, mouse
  • Paclitaxel
  • Gefitinib

Associated data

  • GEO/GSE4824