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

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.

SUBMITTER: Zhou BB

PROVIDER: S-EPMC4451119 | biostudies-literature | 2006 Jul

REPOSITORIES: biostudies-literature

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

Zhou Bin-Bing S BB Peyton Michael M He Biao B Liu Changnian C Girard Luc L Caudler Eian E Lo Yvonne Y Baribaud Frederic F Mikami Iwao I Reguart Noemi N Yang Gengjie G Li Yanlong Y Yao Wenqing W Vaddi Kris K Gazdar Adi F AF Friedman Steven M SM Jablons David M DM Newton Robert C RC Fridman Jordan S JS Minna John D JD Scherle Peggy A PA

Cancer cell 20060701 1

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 Er ...[more]

PMID: 16843264

Dataset Information

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

Publications

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

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