title: The epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 (Iressa) suppresses c-Src and Pak1 pathways and invasiveness of human cancer cells.
abstract: OBJECTIVE
  Abnormalities in the expression and signaling pathways downstream of the epidermal growth factor receptor (EGFR) contribute to the progression, invasion, and maintenance of the malignant phenotype in human cancers, including those of the head and neck and breast. Accordingly, agents such as the EGFR tyrosine kinase inhibitor (EGFR-TKI) ZD1839 (Iressa) are promising, biologically based treatments that are in various stages of preclinical and clinical development. The process of tumor progression requires, among other steps, increased transformation, directional migration, and enhanced cell survival; this study explored the effect of ZD1839 on the stimulation of c-Src and p21-activated kinase 1 (Pak1), which are vital for transformation, directional motility, and cell survival of cancer cells.
  
  
  METHODS
  We examined the effect of ZD1839 on biochemical and functional assays indicative of directional motility and cell survival, using human head and neck squamous cancer cells and breast cancer cells.
  
  
  RESULTS
  ZD1839 effectively inhibited c-Src activation and Pak1 activity in exponentially growing cancer cells. In addition, ZD1839 suppressed EGF-induced stimulation of EGFR autophosphorylation on Y1086 and Grb2-binding Y1068 sites, c-Src phosphorylation on Y215, and Pak1 activity. ZD1839 also blocked EGF-induced cytoskeleton remodeling, redistribution of activated EGFR, and in vitro invasiveness of cancer cells.
  
  
  CONCLUSIONS
  These studies suggest that the EGFR-TKI ZD1839 may cause potent inhibition of the Pak1 and c-Src pathways and, therefore, have potential to affect the invasiveness of human cancer cells deregulated in these growth factor receptor pathways.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Zhibo
authors.initials: Z
authors.lastname: Yang
authors.forename: Rozita
authors.initials: R
authors.lastname: Bagheri-Yarmand
authors.forename: Rui-An
authors.initials: RA
authors.lastname: Wang
authors.forename: Liana
authors.initials: L
authors.lastname: Adam
authors.forename: Vali Vassiliki
authors.initials: VV
authors.lastname: Papadimitrakopoulou
authors.forename: Gary L
authors.initials: GL
authors.lastname: Clayman
authors.forename: Adel
authors.initials: A
authors.lastname: El-Naggar
authors.forename: Reuben
authors.initials: R
authors.lastname: Lotan
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Barnes
authors.forename: Waun Ki
authors.initials: WK
authors.lastname: Hong
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D000081247:CSK Tyrosine-Protein Kinase; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D003599:Cytoskeleton / Q000378:metabolism; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D000077156:Gefitinib; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008856:Microscopy, Fluorescence; D009361:Neoplasm Invasiveness; D010641:Phenotype; D010766:Phosphorylation; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction; D014162:Transfection; D016596:Vinculin / Q000378:metabolism; D054462:p21-Activated Kinases; D019061:src-Family Kinases
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D016596:Vinculin; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; C515903:PAK1 protein, human; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D000077156:Gefitinib