PMID- 15329413 OWN - NLM STAT- MEDLINE DCOM- 20040930 LR - 20241219 IS - 0027-8424 (Print) IS - 1091-6490 (Electronic) IS - 0027-8424 (Linking) VI - 101 IP - 36 DP - 2004 Sep 7 TI - EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. PG - 13306-11 AB - 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. FAU - Pao, William AU - Pao W AD - Program in Cancer Biology and Genetics and Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA. paow@mskcc.org FAU - Miller, Vincent AU - Miller V FAU - Zakowski, Maureen AU - Zakowski M FAU - Doherty, Jennifer AU - Doherty J FAU - Politi, Katerina AU - Politi K FAU - Sarkaria, Inderpal AU - Sarkaria I FAU - Singh, Bhuvanesh AU - Singh B FAU - Heelan, Robert AU - Heelan R FAU - Rusch, Valerie AU - Rusch V FAU - Fulton, Lucinda AU - Fulton L FAU - Mardis, Elaine AU - Mardis E FAU - Kupfer, Doris AU - Kupfer D FAU - Wilson, Richard AU - Wilson R FAU - Kris, Mark AU - Kris M FAU - Varmus, Harold AU - Varmus H LA - eng GR - T32 CA009512/CA/NCI NIH HHS/United States GR - CA009512/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. DEP - 20040825 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Quinazolines) RN - DA87705X9K (Erlotinib Hydrochloride) RN - EC 2.7.10.1 (ErbB Receptors) RN - S65743JHBS (Gefitinib) SB - IM MH - Adenocarcinoma/genetics MH - Amino Acid Sequence MH - Base Sequence MH - Carcinoma, Non-Small-Cell Lung/genetics MH - ErbB Receptors/antagonists & inhibitors/*genetics MH - Erlotinib Hydrochloride MH - Female MH - Gefitinib MH - Humans MH - Lung Neoplasms/*drug therapy/*genetics MH - Male MH - Molecular Sequence Data MH - *Mutation MH - Quinazolines/*therapeutic use PMC - PMC516528 EDAT- 2004/08/27 05:00 MHDA- 2004/10/01 05:00 PMCR- 2005/03/07 CRDT- 2004/08/27 05:00 PHST- 2004/08/27 05:00 [pubmed] PHST- 2004/10/01 05:00 [medline] PHST- 2004/08/27 05:00 [entrez] PHST- 2005/03/07 00:00 [pmc-release] AID - 0405220101 [pii] AID - 10113306 [pii] AID - 10.1073/pnas.0405220101 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13306-11. doi: 10.1073/pnas.0405220101. Epub 2004 Aug 25.