Author/Authors :
Zhou، نويسنده , , Bin-Bing S. and Peyton، نويسنده , , Michael and He، نويسنده , , Biao and Liu، نويسنده , , Changnian and Girard، نويسنده , , Luc and Caudler، نويسنده , , Eian and Lo، نويسنده , , Yvonne and Baribaud، نويسنده , , Frederic and Mikami، نويسنده , , Iwao and Reguart، نويسنده , , Noemi and Yang، نويسنده , , Gengjie and Li، نويسنده , , Yanlong and Yao، نويسنده , , Wenqing and Vaddi، نويسنده , , Kris and Gazdar، نويسنده , , Adi F. and Friedman، نويسنده , , Steven M. and Jablons، نويسنده , , David M. and Newton، نويسنده , , Robert C. and Fridman، نويسنده , , Jordan S. and Minna، نويسنده , , John D. and Scherle، نويسنده , , Peggy A.، نويسنده ,
Abstract :
Summary
cribe 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.
