{"doi":"10.1073/pnas.0405220101","title":"EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib","abstract":"Somatic mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene are reportedly associated with sensitivity of lung cancers to gefitinib (Iressa), kinase inhibitor. In-frame deletions occur in exon 19, whereas point mutations occur frequently in codon 858 (exon 21). We found from sequencing the EGFR TK domain that 7 of 10 gefitinib-sensitive tumors had similar types of alterations; no mutations were found in eight gefitinib-refractory tumors (P = 0.004). Five of seven tumors sensitive to erlotinib (Tarceva), a related kinase inhibitor for which the clinically relevant target is undocumented, had analogous somatic mutations, as opposed to none of 10 erlotinib-refractory tumors (P = 0.003). Because most mutation-positive tumors were adenocarcinomas from patients who smoked <100 cigarettes in a lifetime (\"never smokers\"), we screened EGFR exons 2-28 in 15 adenocarcinomas resected from untreated never smokers. Seven tumors had TK domain mutations, in contrast to 4 of 81 non-small cell lung cancers resected from untreated former or current smokers (P = 0.0001). Immunoblotting of lysates from cells transiently transfected with various EGFR constructs demonstrated that, compared to wild-type protein, an exon 19 deletion mutant induced diminished levels of phosphotyrosine, whereas the phosphorylation at tyrosine 1092 of an exon 21 point mutant was inhibited at 10-fold lower concentrations of drug. Collectively, these data show that adenocarcinomas from never smokers comprise a distinct subset of lung cancers, frequently containing mutations within the TK domain of EGFR that are associated with gefitinib and erlotinib sensitivity.","journal":"Proceedings of the National Academy of Sciences","year":2004,"id":152,"datarank":17.785191228530966,"base_score":8.37516869138682,"endowment":8.37516869138682,"self_citation_contribution":1.2562753037080232,"citation_network_contribution":16.528915924822943,"self_endowment_contribution":1.2562753037080232,"citer_contribution":16.528915924822943,"corpus_percentile":88.1,"corpus_rank":2398,"citation_count":4337,"citer_count":156,"citers_with_citation_signal":156,"citers_with_endowment":156,"datacite_reuse_total":0,"is_dataset":false,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2004-08-25","authors":[{"id":1261,"name":"Katerina Politi","orcid":"0000-0001-6064-4527","position":4,"is_corresponding":false},{"id":1262,"name":"Inderpal Sarkaria","orcid":null,"position":5,"is_corresponding":false},{"id":1263,"name":"Bhuvanesh Singh","orcid":"0000-0003-1457-0066","position":6,"is_corresponding":false},{"id":1264,"name":"Robert Heelan","orcid":null,"position":7,"is_corresponding":false},{"id":1265,"name":"Valerie Rusch","orcid":null,"position":8,"is_corresponding":false},{"id":1266,"name":"Lucinda Fulton","orcid":"0000-0001-6429-4288","position":9,"is_corresponding":false},{"id":1268,"name":"Doris Kupfer","orcid":null,"position":11,"is_corresponding":false},{"id":1796,"name":"George M. 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