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 on...

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Bibliographic Details
Published in:	Cancer cell Vol. 10; no. 1; pp. 39 - 50
Main Authors:	Zhou, Bin-Bing S., Peyton, Michael, He, Biao, Liu, Changnian, Girard, Luc, Caudler, Eian, Lo, Yvonne, Baribaud, Frederic, Mikami, Iwao, Reguart, Noemi, Yang, Gengjie, Li, Yanlong, Yao, Wenqing, Vaddi, Kris, Gazdar, Adi F., Friedman, Steven M., Jablons, David M., Newton, Robert C., Fridman, Jordan S., Minna, John D., Scherle, Peggy A.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-07-2006
Subjects:	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 Female 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, Epidermal Growth Factor - genetics Receptor, Epidermal Growth Factor - metabolism Receptor, ErbB-3 - metabolism Signal Transduction - drug effects SIGNALING Spiro Compounds - pharmacology Spiro Compounds - therapeutic use Xenograft Model Antitumor Assays SIGNALING
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Present address: Tanox, Inc., 10555 Stella Link Road, Houston, Texas 77025.
ISSN:	1535-6108 1878-3686
DOI:	10.1016/j.ccr.2006.05.024