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 erlotinibrefractory 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.

Molecular pathology of lung cancer: key to personalized medicine

“…85 EGFR mutations are generally associated with sensitivity to TKI therapy. 71,87 Both retrospective and prospective studies have demonstrated that lung adenocarcinoma patients carrying such an EGFR mutation and who were treated with TKIs had significantly higher response rates and longer progression-free survival than patients without an EGFR mutation, [5][6][7]25,29,71,83,85,87,88 with some patients experiencing rapid, complete, or partial responses that were persistant. 55 Jackman et al 85 studied 223 chemotherapy-naïve patients with advanced lung cancer of non-small cell type, among which 86% were adenocarcinomas.…”

“…4 In recent years, attention has been paid to the role that 'driver mutations,' such as epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), have in the tumorigenesis of adenocarcinomas, and their potential use as targets for therapy. [5][6][7][8][9] Recent data suggest EGFR may also serve as a prognostic factor, in addition to its role as a predictive factor, as patients-bearing EGFR mutations have shown favorable clinical outcomes even with conventional chemotherapy. [10][11][12][13] EGFR and members of its family have an important role in carcinogenesis through their involvement in the modulation of cell proliferation, apoptosis, cell motility, and neovascularization.…”

Smoker and non-smoker lung adenocarcinoma is characterized by distinct tumor immune microenvironments

“…Most lung cancer results from multiple changes in the genome of susceptible pulmonary cells caused by exposure to carcinogens found in tobacco smoke, the environment, and the workplace. Patients exposed to a smoking environment had more frequent gene mutations, such as the epidermal growth factor receptor ( EGFR ) gene, 3 the K-ras gene, 4 and the p53 gene. 5,6 …”

Epidermal growth factor receptor mutations detected by denaturing high‐performance liquid chromatography in nonsmall cell lung cancer

“…The other is a point mutation in exon 21 (2573T>G) that results in substitution of leucine by arginine at codon 858 (L858R). [4][5][6][7][8][9][10] Other much less common mutations have also been described in exons 18, 20, and 21.…”