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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
Open accessAbstract
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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“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]
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“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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“TKIs have been associated with longer progression-free survival (PFS) than chemotherapy in advanced NSCLC with EGFR mutations (2,4).”
Background
Metadata
- 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
- 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
- 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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