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EGF receptor in relation to tumor development: molecular basis of responsiveness of cancer cells to EGFR‐targeting tyrosine kinase inhibitors
Author(s) -
Takeuchi Kenji,
Ito Fumiaki
Publication year - 2010
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2009.07450.x
Subject(s) - gefitinib , cancer research , receptor tyrosine kinase , protein kinase b , tyrosine kinase , platelet derived growth factor receptor , ror1 , tropomyosin receptor kinase c , proto oncogene tyrosine protein kinase src , epidermal growth factor receptor , signal transduction , biology , microbiology and biotechnology , chemistry , biochemistry , receptor , growth factor
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.