EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib

Pao, William; Miller, Vincent; Zakowski, Maureen; Doherty, Jennifer; Politi, Katerina; Sarkaria, Inderpal; Singh, Bhuvanesh; Heelan, Robert; Rusch, Valerie; Fulton, Lucinda; Mardis, Elaine; Kupfer, Doris; Wilson, Richard; Kris, Mark; Varmus, Harold

doi:10.1073/pnas.0405220101

Cited by 4,338Lung Cancer Treatments and MutationsHER2/EGFR in Cancer ResearchLung Cancer Research Studies

EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib

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Pao, William, Miller, Vincent, Zakowski, Maureen, Doherty, Jennifer, Politi, Katerina, Sarkaria, Inderpal, Singh, Bhuvanesh, Heelan, Robert +7 more·2004·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0405220101PMC PMC516528

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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.

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Reduced sensitivity to gefitinib or erlotinib in NSCLC was linked to EGFR-specific activating mutations.
“Afterwards, studies revealed that the reduced sensitivity to gefitinib or erlotinib in NSCLC was linked to EGFR-specific activating mutations.112–116”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [114]
Somatic, activating mutations in EGFR were discovered in a subset of non-small cell lung cancers in 2004.
“The causal role of EGFR in tumorigenesis was further solidified in 2004 when somatic, activating mutations in EGFR were discovered in a subset of non-small cell lung cancers (NSCLC) (Lynch et al., 2004; Paez et al., 2004; Pao et al., 2004) (Table 1).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Pao et al., 2004

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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.
Affiliations: Memorial Sloan Kettering Cancer Center (US)
ORCID: Pao, William
Miller, Vincent
Zakowski, Maureen
Doherty, Jennifer
Politi, Katerina
Singh, Bhuvanesh
Rusch, Valerie
Mardis, Elaine
Wilson, Richard
Kris, Mark
Varmus, Harold
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2004-08-25
Volume: 101
Issue: 36
Pages: 13306-13311
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.0405220101
PMC: PMC516528
OpenAlex: W2139236349
Cited by: 4,338
References: 31
Citations by year: 2026: 40 · 2025: 59 · 2024: 68 · 2023: 122 · 2022: 129 · 2021: 108 · 2020: 134 · 2019: 138 · 2018: 188 · 2017: 178 · 2016: 220 · 2015: 280 · 2014: 272 · 2013: 289 · 2012: 284
FWCI: 227.94
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: AstraZeneca
Memorial Sloan-Kettering Cancer Center
Alvin J. Siteman Cancer Center
U.S. Food and Drug Administration
Genentech
National Cancer Institute (CA009512, T32CA009512)
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
Keywords: EGFR mutation, epidermal growth factor receptor, non-small cell lung cancer, never smokers, gefitinib sensitivity, tyrosine kinase inhibitors, exon 19 deletion, lung adenocarcinoma, tyrosine kinase domain, tyrosine phosphorylation
MeSH terms: Erlotinib Hydrochloride, Gefitinib, Adenocarcinoma, Amino Acid Sequence, Base Sequence, Carcinoma, Non-Small-Cell Lung, Female, Humans, Lung Neoplasms, Male, Molecular Sequence Data, Mutation, Quinazolines, ErbB Receptors

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EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib

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