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.