The epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 (Iressa) suppresses c-Src and Pak1 pathways and invasiveness of human cancer cells

Clin Cancer Res. 2004 Jan 15;10(2):658-67. doi: 10.1158/1078-0432.ccr-0382-03.

Abstract

Purpose: 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.

Experimental design: 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Blotting, Western
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / pathology
  • CSK Tyrosine-Protein Kinase
  • Carcinoma, Squamous Cell / drug therapy
  • Carcinoma, Squamous Cell / pathology
  • Cell Line, Tumor
  • Cell Movement
  • Cell Survival
  • Cytoskeleton / metabolism
  • Disease Progression
  • Dose-Response Relationship, Drug
  • Epidermal Growth Factor / metabolism
  • ErbB Receptors / metabolism
  • Gefitinib
  • Head and Neck Neoplasms / metabolism
  • Head and Neck Neoplasms / pathology
  • Humans
  • Microscopy, Fluorescence
  • Neoplasm Invasiveness
  • Phenotype
  • Phosphorylation
  • Precipitin Tests
  • Protein Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases / metabolism*
  • Quinazolines / pharmacology*
  • Signal Transduction
  • Transfection
  • Vinculin / metabolism
  • p21-Activated Kinases
  • src-Family Kinases

Substances

  • Antineoplastic Agents
  • Quinazolines
  • Vinculin
  • Epidermal Growth Factor
  • ErbB Receptors
  • Protein-Tyrosine Kinases
  • CSK Tyrosine-Protein Kinase
  • src-Family Kinases
  • CSK protein, human
  • PAK1 protein, human
  • Protein Serine-Threonine Kinases
  • p21-Activated Kinases
  • Gefitinib