Synergistic inhibition with a dual epidermal growth factor receptor/HER-2/neu tyrosine kinase inhibitor and a disintegrin and metalloprotease inhibitor.

Abstract

The ErbB family of receptors is overexpressed in numerous human tumors. Overexpression correlates with poor prognosis and resistance to therapy. Use of ErbB-specific antibodies to the receptors (Herceptin or Erbitux) or ErbB-specific small-molecule inhibitors of the receptor tyrosine kinase activity (Iressa or Tarceva) has shown clinical efficacy in several solid tumors. An alternative method of affecting ErbB-initiated tumor growth and survival is to block sheddase activity. Sheddase activity is responsible for cleavage of multiple ErbB ligands and receptors, a necessary step in availability of the soluble, active form of the ligand and a constitutively activated ligand-independent receptor. This sheddase activity is attributed to the ADAM (a disintegrin and metalloprotease) family of proteins. ADAM 10 is the main sheddase of epidermal growth factor (EGF) and HER-2/neu cleavage, whereas ADAM17 is required for cleavage of additional EGF receptor (EGFR) ligands (transforming growth factor-alpha, amphiregulin, heregulin, heparin binding EGF-like ligand). This study has shown that addition of INCB3619, a potent inhibitor of ADAM10 and ADAM17, reduces in vitro HER-2/neu and amphiregulin shedding, confirming that it interferes with both HER-2/neu and EGFR ligand cleavage. Combining INCB3619 with a lapatinib-like dual inhibitor of EGFR and HER-2/neu kinases resulted in synergistic growth inhibition in MCF-7 and HER-2/neu-transfected MCF-7 human breast cancer cells. Combining the INCB7839 second-generation sheddase inhibitor with lapatinib prevented the growth of HER-2/neu-positive BT474-SC1 human breast cancer xenografts in vivo. These results suggest that there may be an additional clinical benefit of combining agents that target the ErbB pathways at multiple points.

• Authors: Lois Witters, Peggy Scherle, Steven Friedman, Jordan Fridman, Eian Caulder, Robert Newton, Allan Lipton
• Journal: Cancer research (Cancer Res) Vol. 68 Issue 17 Pg. 7083-9 (Sep 01 2008) ISSN: 1538-7445 [Electronic] United States
• PMID: 18757423 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Disintegrins
• INCB3619
• Piperidines
• Protease Inhibitors
• Spiro Compounds
• ERBB2 protein, human
• Receptor, ErbB-2
• Metalloproteases

Topics

• Animals
• Breast Neoplasms (metabolism, pathology)
• Cell Division (drug effects)
• Cell Line, Tumor
• Disintegrins (antagonists & inhibitors)
• Female
• Humans
• Metalloproteases (antagonists & inhibitors)
• Mice
• Piperidines (pharmacology)
• Protease Inhibitors (pharmacology)
• Receptor, ErbB-2 (antagonists & inhibitors)
• Signal Transduction
• Spiro Compounds (pharmacology)