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


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.

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@article{Zhou2006TargetingAL, title={Targeting ADAM-mediated ligand cleavage to inhibit HER3 and EGFR pathways in non-small cell lung cancer.}, author={Bin-Bing S. Zhou and Michael Peyton and Biao He and Changnian Liu and Luc Girard and Eian Caudler and Yvonne Y Lo and Fr{\'e}d{\'e}ric Baribaud and Iwao Mikami and Noem{\'i} Reguart and Gengjie Yang and Yanlong Li and Wenqing Yao and Kris Vaddi and Adi F. Gazdar and Steven Morgan Friedman and David Mark Jablons and Robert C. Newton and Jordan S . Fridman and John D. Minna and Peggy A. Scherle}, journal={Cancer cell}, year={2006}, volume={10 1}, pages={39-50} }