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

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

  • Cancer Cell. 2006 Jul;10(1):39-50. doi: 10.1016/j.ccr.2006.05.024.
Bin-Bing S Zhou 1,  Michael Peyton,  Biao He,  Changnian Liu,  Luc Girard,  Eian Caudler,  Yvonne Lo,  Frederic Baribaud,  Iwao Mikami,  Noemi Reguart,  Gengjie Yang,  Yanlong Li,  Wenqing Yao,  Kris Vaddi,  Adi F Gazdar,  Steven M Friedman,  David M Jablons,  Robert C Newton,  Jordan S Fridman,  John D Minna,  Peggy A Scherle
Affiliations

Affiliation

  • 1 Drug Discovery, Incyte Corporation, Experimental Station, Route 141 and Henry Clay Road, Building 400, Wilmington, Delaware 19880, USA. [email protected]
PMID: 16843264 DOI: 10.1016/j.ccr.2006.05.024
Abstract

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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