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

Bin Bing S Zhou, 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. MinnaPeggy A. Scherle

Research output: Contribution to journalArticlepeer-review

325 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)39-50
Number of pages12
JournalCancer Cell
Issue number1
StatePublished - Jul 2006



ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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