EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib Journal Article
| Authors: | Pao, W.; Miller, V.; Zakowski, M.; Doherty, J.; Politi, K.; Sarkaria, I.; Singh, B.; Heelan, R.; Rusch, V.; Fulton, L.; Mardis, E.; Kupfer, D.; Wilson, R.; Kris, M.; Varmus, H. |
| Article 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. |
| Keywords: | controlled study; human tissue; protein phosphorylation; gene mutation; major clinical study; exon; gene deletion; mutation; erlotinib; drug targeting; protein domain; adenocarcinoma; gene targeting; imatinib; carcinoma, non-small-cell lung; lung neoplasms; epidermal growth factor receptor; lung cancer; smoking; receptor, epidermal growth factor; tyrosine; wild type; protein tyrosine kinase inhibitor; lung adenocarcinoma; amino acid sequence; molecular sequence data; gefitinib; immunoblotting; base sequence; point mutation; quinazolines; genetic screening; drug sensitivity; deletion mutant; cell lysate; gene construct; phosphotyrosine; tyrosine kinase domain; humans; human; male; female; priority journal; article |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 101 |
| Issue: | 36 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2004-09-07 |
| Start Page: | 13306 |
| End Page: | 13311 |
| Language: | English |
| DOI: | 10.1073/pnas.0405220101 |
| PROVIDER: | scopus |
| PMCID: | PMC516528 |
| PUBMED: | 15329413 |
| DOI/URL: | |
| Notes: | Proc. Natl. Acad. Sci. U. S. A. -- Cited By (since 1996):2355 -- Export Date: 16 June 2014 -- CODEN: PNASA -- Source: Scopus |
