Distinctive activation patterns in constitutively active and gefitinib-sensitive EGFR mutants

• Published in: Oncogene Vol. 25; no. 8; pp. 1205 - 1215
• Main Authors: CHEN, Y.-R, FU, Y.-N, LIN, C.-H, YANG, S.-T, HU, S.-F, CHEN, Y.-T, TSAI, S.-F, HUANG, S.-F
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 23-02-2006; Nature Publishing Group
• Subjects: Animals; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cercopithecus aethiops; Chemotherapy; COS Cells; Deletion mutant; Epidermal growth factor; Epidermal Growth Factor - pharmacology; Epidermal growth factor receptors; Epidermal growth factors; Fundamental and applied biological sciences. Psychology; Gefitinib; Immunoprecipitation; Kinases; Ligands; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Medical research; Molecular and cellular biology; Mutants; Mutation; Mutation - genetics; Non-small cell lung cancer; Non-small cell lung carcinoma; Pathology; Phosphorylation; Phosphorylation - drug effects; Quinazolines - therapeutic use; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - metabolism; Research centers; Tumor Cells, Cultured; Tumorigenesis; Tyrosine; Tyrosine - metabolism; Ubiquitin - metabolism; Ubiquitination; Taiwan; Antineoplastic agent; Tyrosine; Phosphorylation; NSCLC; Activation; Mutation; tyrosine phosphorylation; Gefitinib; Carcinogenesis; EGFR
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1209159

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.