EGFR Mutation and Resistance of Non–Small-Cell Lung Cancer to Gefitinib

Kobayashi, Susumu; Boggon, Titus J.; Dayaram, Tajhal; Jänne, Pasi A.; Kocher, Olivier; Meyerson, Matthew; Johnson, Bruce E.; Eck, Michael J.; Tenen, Daniel G.; Halmos, Balázs

doi:10.1056/nejmoa044238

Cited by 3,964Lung Cancer Treatments and MutationsHER2/EGFR in Cancer ResearchCancer Genomics and Diagnostics

EGFR Mutation and Resistance of Non–Small-Cell Lung Cancer to Gefitinib

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Kobayashi, Susumu, Boggon, Titus J., Dayaram, Tajhal, Jänne, Pasi A., Kocher, Olivier, Meyerson, Matthew, Johnson, Bruce E., Eck, Michael J. +2 more·2005·New England Journal of Medicine

DOI 10.1056/nejmoa044238

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Abstract

Mutations of the epidermal growth factor receptor (EGFR) gene have been identified in specimens from patients with non-small-cell lung cancer who have a response to anilinoquinazoline EGFR inhibitors. Despite the dramatic responses to such inhibitors, most patients ultimately have a relapse. The mechanism of the drug resistance is unknown. Here we report the case of a patient with EGFR-mutant, gefitinib-responsive, advanced non-small-cell lung cancer who had a relapse after two years of complete remission during treatment with gefitinib. The DNA sequence of the EGFR gene in his tumor biopsy specimen at relapse revealed the presence of a second point mutation, resulting in threonine-to-methionine amino acid change at position 790 of EGFR. Structural modeling and biochemical studies showed that this second mutation led to gefitinib resistance.

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The EGFR T790M gatekeeper mutation is a leading cause of resistance to first- and second-generation EGFR inhibitors in EGFR-mutant lung cancers.
“the EGFR T790M gatekeeper mutation, is a leading cause of resistance to first- and second-generation EGFR inhibitors [11,12].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [11]
The major mechanism of acquired resistance to first-generation EGFR-TKIs is the occurrence of secondary EGFR kinase domain mutation in exon 20, the T790M substitution, which accounts for about half of the cases.
“The major mechanism of acquired resistance to first-generation EGFR-TKIs is the occurrence of secondary EGFR kinase domain mutation in exon 20, the T790M substitution, which accounts for about half of the cases.”
From Mechanisms of resistance to EGFR-targeted drugs: lung cancer (2016) · cites this paper as [13]
T790M is the most common acquired resistance mechanism and is detected in more than half of patients after progression.
“However, it is now well established that acquisition of a second mutation in EGFR, resulting in substitution of threonine at the “gatekeeper” amino acid 790 to methionine (T790M) is the most common resistance mechanism and is detected in tumor cells from more than 50% of patients after disease progression (20, 21).”
From AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer (2014) · cites this paper as [20]
EGFR T790M mutations account for about 50% of acquired resistance to gefitinib or erlotinib.
“EGFR T790M mutations account for about 50% of acquired resistance to gefitinib or erlotinib [24, 25].”
From In vitro modeling to determine mutation specificity of EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants in non-small-cell lung cancer (2015) · cites this paper as [24]
The secondary mutation T790M accounts for approximately 50%-60% of acquired resistance to first-generation EGFR-TKIs.
“The secondary mutation T790M accounts for approximately 50%–60% of acquired resistance to 1G‐TKI.34, 35”
From Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy (2016) · cites this paper as [34]

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Authors: Kobayashi, S., Boggon, T. J., Dayaram, T., Jänne, P. A., Kocher, O., Meyerson, M., Johnson, B. E., Eck, M. J., Tenen, D. G., & Halmos, B.
Affiliations: Beth Israel Deaconess Medical Center (US)
Harvard University (US)
Brigham and Women's Hospital (US)
ORCID: Kobayashi, Susumu
Boggon, Titus J.
Kocher, Olivier
Meyerson, Matthew
Johnson, Bruce E.
Eck, Michael J.
Tenen, Daniel G.
Halmos, Balázs
Venue: New England Journal of Medicine
Publisher: Massachusetts Medical Society
Published: 2005-02-24
Volume: 352
Issue: 8
Pages: 786-792
ISSN: 0028-4793 (ISSN-L)
1533-4406
DOI: 10.1056/nejmoa044238
OpenAlex: W2003984225
Cited by: 3,964
References: 2
Citations by year: 2026: 90 · 2025: 89 · 2024: 105 · 2023: 147 · 2022: 158 · 2021: 193 · 2020: 194 · 2019: 196 · 2018: 242 · 2017: 248 · 2016: 248 · 2015: 257 · 2014: 228 · 2013: 242 · 2012: 211
FWCI: 154.43
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: New England Journal of Medicine (publishedVersion)
PubMed (publishedVersion)
Funders: National Cancer Institute (1K12CA87723-01, PA20-CA090578-01A1, K12CA087723)
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords: EGFR mutation, gefitinib resistance, non-small cell lung cancer, EGFR tyrosine kinase inhibitors, anilinoquinazolines, T790M mutation, relapse, drug resistance mechanisms, structural modeling
MeSH terms: Erlotinib Hydrochloride, Gefitinib, Aged, Antineoplastic Agents, Biopsy, Carcinoma, Non-Small-Cell Lung, DNA, Neoplasm, Humans, Lung Neoplasms, Male, Models, Structural, Neoplasm Recurrence, Local, Quinazolines, RNA, Neoplasm, Molecular Structure, Point Mutation, Sequence Analysis, DNA, Sequence Analysis, RNA, Drug Resistance, Neoplasm, ErbB Receptors

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EGFR Mutation and Resistance of Non–Small-Cell Lung Cancer to Gefitinib

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