The DOI matches its Crossref record; 31 of the 31 references it cites were found in a registry or an index.
Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non–Small-Cell Lung Cancer to Gefitinib
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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EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy
Paez, J. G., Jänne, P. A., Lee, J. C., Tracy, S., Greulich, H., Gabriel, S., Herman, P., Kaye, F. J., Lindeman, N., Boggon, T. J., et al. (2004) · Science · doi:10.1126/science.1099314 · Cited by 9,368
Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma
Mok, T. S., Wu, Y.-L., Thongprasert, S., Yang, C.-H., Chu, D.-T., Saijo, N., Sunpaweravong, P., Han, B., Margono, B., Ichinose, Y., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0810699 · Cited by 8,261
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Gefitinib or Chemotherapy for Non–Small-Cell Lung Cancer with Mutated EGFR
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Metadata
- 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
- 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
- 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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