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 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.
Zhou
Bin-Bing S
BB
Drug Discovery, Incyte Corporation, Experimental Station, Route 141 and Henry Clay Road, Building 400, Wilmington, Delaware 19880, USA. binbing_s_zhou@yahoo.com
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
D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D000077156:Gefitinib; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008954:Models, Biological; D017239:Paclitaxel / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D020893:Receptor, ErbB-3 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013141:Spiro Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
C513090:INCB3619; D008024:Ligands; D010880:Piperidines; D011480:Protease Inhibitors; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D013141:Spiro Compounds; D066246:ErbB Receptors; D020893:Receptor, ErbB-3; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse; D017239:Paclitaxel; D000077156:Gefitinib