%0 Journal Article
%T Evidence for efficient phosphorylation of EGFR and rapid endocytosis of phosphorylated EGFR via the early/late endocytic pathway in a gefitinib-sensitive non-small cell lung cancer cell line
%A Yukio Nishimura
%A Kiyoko Yoshioka
%A Biborka Bereczky
%A Kazuyuki Itoh
%J Molecular Cancer
%D 2008
%I BioMed Central
%R 10.1186/1476-4598-7-42
%X The epidermal growth factor receptor (EGFR) is a prototypical member of the ErbB family of tyrosine kinases and plays an important role in the pathogenesis of different tumors; therefore, therapies directed at inhibiting EGFR function have potential as anticancer treatments [1,2]. Each EGFR comprises an extracellular binding domain and a cytoplasmic domain with tyrosine kinase activity [3]. Following ligand binding, the EGFR is dimerized and the intracellular tyrosine kinase region is activated, causing receptor tyrosine autophosphorylation and transphosphorylation of another receptor monomer [4]. These events lead to the recruitment and phosphorylation of several intracellular substrates and the subsequent transmission of extracellular signals to the nucleus via an intracellular signaling network [4,5].Gefitinib (Iressa, ZD1839) is a selective EGFR tyrosine kinase inhibitor that functions by competing with ATP for binding to the tyrosine kinase domain of the receptor, and it blocks the signal transduction pathways implicated in the proliferation and survival of cancer cells [6-9]. It has exhibited significant antitumor activity against a broad range of mouse tumor xenograft models in vivo [10] and tumor cell lines in vitro [11]. A recent in vitro study demonstrated that of the 9 non-small cell lung cancer (NSCLC) cell lines examined, the PC9 cell line was most sensitive to the effect of gefitinib when assayed under basal growth conditions for EGFR phosphorylation and activation of EGFR downstream effectors such as AKT and those in the ERK1/2 pathway, which are required for its survival and proliferation [11]. This suggests that the mechanism underlying the sensitivity of the EGFR pathway could be useful in predicting the potential effectiveness of gefitinib in NSCLC patients. Inefficient EGFR down regulation was observed in the gefitinib-resistant cell line QG56, whereas rapid down regulation occurred in the gefitinib-sensitive cell line PC9, wherein the cells were
%U http://www.molecular-cancer.com/content/7/1/42