Distinctive activation patterns in constitutively active and gefitinib-sensitive EGFR mutants.
Oncogene
; 25(8): 1205-15, 2006 Feb 23.
Article
em En
| MEDLINE
| ID: mdl-16205628
ABSTRACT
Mutations in the kinase domain of epidermal growth factor receptor (EGFR) are associated with clinical responsiveness to gefitinib in patients with non-small-cell lung cancers (NSCLC). Recently, we have identified many novel EGFR mutations in NSCLC tissues. In this study, we found that gefitinib could suppress the tyrosine phosphorylation of most EGFR mutants better than the wild-type receptor. However, gefitinib had quite variable growth-suppressive effects on different EGFR mutant-expressing cells. All tested EGFR mutants have high basal phosphorylation at multiple tyrosine residues. Upon EGF stimulation, the mutated EGFRs did not have apparently stronger phosphorylation at tyrosines 845, 992, 1,068, and 1,173 than the wild-type receptor. However, stronger phosphorylation at tyrosine 1,045 was observed in the S768I, L861Q, E709G, and G719S mutants. The E746-A750 deletion mutant was less responsive to EGF than the wild-type and other mutant receptors. The S768I, L861Q, E709G, and G719S mutants were refractory to EGF-induced ubiquitination and had more sustained tyrosine phosphorylation. E709G and G719S also lacked EGF-induced receptor downregulation. Our results indicate that, in addition to sensitivity to gefitinib, EGFR mutations also caused various changes in EGFR's regulatory mechanisms, which may contribute to the constitutive activation of EGFR mutants and oncogenesis in NSCLC.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Quinazolinas
/
Receptores ErbB
/
Mutação
/
Antineoplásicos
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Oncogene
Assunto da revista:
BIOLOGIA MOLECULAR
/
NEOPLASIAS
Ano de publicação:
2006
Tipo de documento:
Article
País de afiliação:
Taiwan