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.