Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non–Small-Cell Lung Cancer to Gefitinib

Lynch, Thomas J.; Bell, Daphne W.; Sordella, Raffaella; Gurubhagavatula, Sarada; Okimoto, Ross A.; Brannigan, Brian W.; Harris, Patricia L.; Haserlat, Sara M.; Supko, Jeffrey G.; Haluska, Frank G.; Louis, David N.; Christiani, David C.; Settleman, Jeff; Haber, Daniel A.

doi:10.1056/nejmoa040938

Cited by 11,486Lung Cancer Treatments and MutationsHER2/EGFR in Cancer ResearchLung Cancer Research Studies

Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non–Small-Cell Lung Cancer to Gefitinib

Lynch, Thomas J., Bell, Daphne W., Sordella, Raffaella, Gurubhagavatula, Sarada, Okimoto, Ross A., Brannigan, Brian W., Harris, Patricia L., Haserlat, Sara M. +6 more·2004·New England Journal of Medicine

DOI 10.1056/nejmoa040938

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Abstract

BACKGROUND: Most patients with non-small-cell lung cancer have no response to the tyrosine kinase inhibitor gefitinib, which targets the epidermal growth factor receptor (EGFR). However, about 10 percent of patients have a rapid and often dramatic clinical response. The molecular mechanisms underlying sensitivity to gefitinib are unknown. METHODS: We searched for mutations in the EGFR gene in primary tumors from patients with non-small-cell lung cancer who had a response to gefitinib, those who did not have a response, and those who had not been exposed to gefitinib. The functional consequences of identified mutations were evaluated after the mutant proteins were expressed in cultured cells. RESULTS: Somatic mutations were identified in the tyrosine kinase domain of the EGFR gene in eight of nine patients with gefitinib-responsive lung cancer, as compared with none of the seven patients with no response (P<0.001). Mutations were either small, in-frame deletions or amino acid substitutions clustered around the ATP-binding pocket of the tyrosine kinase domain. Similar mutations were detected in tumors from 2 of 25 patients with primary non-small-cell lung cancer who had not been exposed to gefitinib (8 percent). All mutations were heterozygous, and identical mutations were observed in multiple patients, suggesting an additive specific gain of function. In vitro, EGFR mutants demonstrated enhanced tyrosine kinase activity in response to epidermal growth factor and increased sensitivity to inhibition by gefitinib. CONCLUSIONS: A subgroup of patients with non-small-cell lung cancer have specific mutations in the EGFR gene, which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib. These mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor. Screening for such mutations in lung cancers may identify patients who will have a response to gefitinib.

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In Brief
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No longer in the dark
Hutchinson, E. (2004) · Nature reviews. Cancer · doi:10.1038/nrc1376

Authors: Lynch, T. J., Bell, D. W., Sordella, R., Gurubhagavatula, S., Okimoto, R. A., Brannigan, B. W., Harris, P. L., Haserlat, S. M., Supko, J. G., Haluska, F. G., Louis, D. N., Christiani, D. C., Settleman, J., & Haber, D. A.
Affiliations: Harvard University (US)
ORCID: Lynch, Thomas J.
Bell, Daphne W.
Sordella, Raffaella
Okimoto, Ross A.
Supko, Jeffrey G.
Louis, David N.
Christiani, David C.
Haber, Daniel A.
Venue: New England Journal of Medicine
Publisher: Massachusetts Medical Society
Published: 2004-05-20
Volume: 350
Issue: 21
Pages: 2129-2139
ISSN: 0028-4793 (ISSN-L)
1533-4406
DOI: 10.1056/nejmoa040938
OpenAlex: W2043696829
Cited by: 11,486
References: 31
Citations by year: 2026: 194 · 2025: 220 · 2024: 236 · 2023: 380 · 2022: 328 · 2021: 374 · 2020: 421 · 2019: 388 · 2018: 490 · 2017: 561 · 2016: 616 · 2015: 673 · 2014: 679 · 2013: 691 · 2012: 683
FWCI: 606.47
Type: journal article
Language: en
Open access: closed
Locations: New England Journal of Medicine (publishedVersion)
PubMed (publishedVersion)
Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
Funders: U.S. Public Health Service (P01 95281)
National Cancer Institute (P30-CA0516, R01CA092824, P50CA090578)
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: non-small cell lung cancer, epidermal growth factor receptor, gefitinib, EGFR mutation, tyrosine kinase inhibitors, drug sensitivity, ATP binding site, gain-of-function mutations, tyrosine kinase activity, predictive biomarkers, targeted therapy
MeSH terms: Gefitinib, Adenocarcinoma, Adult, Aged, Aged, 80 and over, Amino Acid Sequence, Antineoplastic Agents, Base Sequence, Carcinoma, Non-Small-Cell Lung, DNA Mutational Analysis, Epidermal Growth Factor, Female, Heterozygote, Humans, Lung Neoplasms, Male, Middle Aged, Molecular Sequence Data, Mutation, Protein-Tyrosine Kinases, Quinazolines, Sequence Deletion, Genes, erbB-1, Drug Resistance, Neoplasm, ErbB Receptors

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Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non–Small-Cell Lung Cancer to Gefitinib

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