title: EGF receptor in relation to tumor development: molecular basis of responsiveness of cancer cells to EGFR-targeting tyrosine kinase inhibitors.
abstract: The function of the epidermal growth factor receptor (EGFR) is dysregulated in various types of malignancy as a result of gene amplification, mutations, or abnormally increased ligand production. Therefore, the tyrosine kinase activity of the EGFR is a promising therapeutic target. EGFR tyrosine kinase inhibitors, such as gefitinib (Iressa), show evident anticancer effects in patients with non-small cell lung cancer. The induction of apoptosis has been considered to be the major mechanism for these gefitinib-mediated anticancer effects. Lung cancer cells harboring mutant EGFRs become dependent on them for their survival and, consequently, undergo apoptosis following the inhibition of EGFR tyrosine kinase by gefitinib. Gefitinib has been shown to inhibit cell survival and growth signaling pathways such as the extracellular signal-regulated kinase 1/2 pathway and the Akt pathway, as a consequence of the inactivation of EGFR. However, the precise downstream signaling molecules of extracellular signal-regulated kinase 1/2 and Akt have not yet been elucidated. In this minireview we have highlighted the effect of tyrosine kinase inhibitors on members of the Bcl-2 family of proteins, which are downstream signaling molecules and serve as the determinants that control apoptosis. We also discuss tyrosine kinase inhibitor-induced apoptosis via c-Jun NH(2)-terminal kinase and p38 mitogen-activated protein kinase.
authors.affiliation: Department of Biochemistry, Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan. takeuchi@pharm.setsunan.ac.jp
authors.forename: Kenji
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Ito
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D000072224:Bcl-2-Like Protein 11; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000502:physiology*; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008565:Membrane Proteins / Q000502:physiology; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D011799:Quinazolines / Q000627:therapeutic use; D051028:bcl-2-Associated X Protein / Q000502:physiology; D051025:bcl-Associated Death Protein / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; C494819:BAD protein, human; C494826:BAX protein, human; C438378:BBC3 protein, human; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D000077156:Gefitinib