The impact of gefitinib on epidermal growth factor receptor signaling pathways in cancer.
The ErbB family of receptor tyrosine kinases, of which the epidermal growth factor receptor (EGFR) is the prototype, is associated with the formation and malignant progression of most of the common solid tumors. These molecules play a key role in a complex network of signal transduction pathways that function in normal development as well as in neoplastic transformation. The EGFR and other family members are therefore promising targets for new anticancer therapies. In normal tissues, EGFR-tyrosine kinase (TK) activity is strictly controlled. However, in tumor cells, there are multiple mechanisms that can lead to increased or inappropriate EGFR-TK activity, including altered expression of EGFR, its ligand, or interacting molecules; decreased deactivation through phosphatases or downregulation; or mutation of the EGFR protein. Novel therapeutic approaches aimed at inhibiting increased EGFR-TK activity include antibodies that block the extracellular ligand-binding site, antibody or ligand fusion proteins that specifically target toxins to the tumor cells, or small-molecule TK inhibitors (TKIs) that act intracellularly to block downstream signal transduction from EGFR. Studies have shown that such blockade can lead to reduced cellular proliferation, inhibition of survival signals, and inhibition of tumor metastasis and angiogenesis. Additionally, some agents, including EGFR antibodies and TKIs such as gefitinib have been demonstrated to be effective against various human solid tumors in preclinical models and have shown activity in advanced non-small-cell lung cancer and other solid tumors.
Averbuch
Steven D
SD
Clinical Research, Oncology, AstraZeneca Pharmaceuticals, Wilmington, DE, USA. steven.averbuch@astrazeneca.com
D000970:Antineoplastic Agents / Q000494:pharmacology*; D066246:ErbB Receptors / Q000187:drug effects* / Q000502:physiology; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D009389:Neovascularization, Pathologic; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib