In vivo inhibition of epidermal growth factor receptor autophosphorylation prevents receptor internalization.
The question whether epidermal growth factor (EGF)-induced receptor endocytosis requires the prior autophosphorylation via the EGF receptor (EGFR) kinase domain has been a matter of long-standing debate. In the airway epithelial cell line NCI-H292, the EGFR kinase domain inhibitor BIBW 2948 BS was found to inhibit both autophosphorylation and subsequent internalization of the endogenous EGFR with similar IC₅₀ values. Applying an ex vivo EGFR internalization assay in a clinical study, the in vivo effect of inhalatively administered BIBW 2948 BS was determined directly at the targeted receptor in airway tissues from COPD patients. In these experiments, the in vivo inhibition of the EGFR kinase domain prevented the EGF-induced internalization of EGFR.
Wolff
Michael
M
Dept. of Lead Discovery, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str.65, D-88397 Biberach, Germany.
Tetzlaff
Kay
K
Nivens
Michael C
MC
Schneider
Franz-Josef
FJ
Jung
Birgit
B
Hohlfeld
Jens
J
Heilker
Ralf
R
D001706:Biopsy; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D004311:Double-Blind Method; D015536:Down-Regulation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D010919:Placebos; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D021381:Protein Transport / Q000187:drug effects; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D010919:Placebos; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors