Acquired Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib Is Associated with a Second Mutation in the EGFR Kinase Domain
Open accessAbstract
BACKGROUND: Lung adenocarcinomas from patients who respond to the tyrosine kinase inhibitors gefitinib (Iressa) or erlotinib (Tarceva) usually harbor somatic gain-of-function mutations in exons encoding the kinase domain of the epidermal growth factor receptor (EGFR). Despite initial responses, patients eventually progress by unknown mechanisms of "acquired" resistance. METHODS AND FINDINGS: We show that in two of five patients with acquired resistance to gefitinib or erlotinib, progressing tumors contain, in addition to a primary drug-sensitive mutation in EGFR, a secondary mutation in exon 20, which leads to substitution of methionine for threonine at position 790 (T790M) in the kinase domain. Tumor cells from a sixth patient with a drug-sensitive EGFR mutation whose tumor progressed on adjuvant gefitinib after complete resection also contained the T790M mutation. This mutation was not detected in untreated tumor samples. Moreover, no tumors with acquired resistance had KRAS mutations, which have been associated with primary resistance to these drugs. Biochemical analyses of transfected cells and growth inhibition studies with lung cancer cell lines demonstrate that the T790M mutation confers resistance to EGFR mutants usually sensitive to either gefitinib or erlotinib. Interestingly, a mutation analogous to T790M has been observed in other kinases with acquired resistance to another kinase inhibitor, imatinib (Gleevec). CONCLUSION: In patients with tumors bearing gefitinib- or erlotinib-sensitive EGFR mutations, resistant subclones containing an additional EGFR mutation emerge in the presence of drug. This observation should help guide the search for more effective therapy against a specific subset of lung cancers.
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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 [21]
The T790M mutation substitutes methionine for threonine at position 790, increases affinity for ATP, and causes resistance to reversible EGFR TKIs such as gefitinib and erlotinib.
“This mutation leads to the substitution of threonine by methionine at position 790, which encodes part of the kinase domain of the receptor and results in increased affinity for ATP, causing resistance to competitive inhibition by reversible EGFR TKIs such as gefitinib and erlotinib [121,122].”
From Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up (2016) · cites this paper as [121]
In EGFR mutant lung cancer, the most common mechanism of acquired resistance to EGFR inhibitors is the development of a mutation in the gatekeeper residue of EGFR, T790M.
“In EGFR mutant lung cancer, the most common mechanism of acquired resistance to EGFR inhibitors is the development of a mutation in the gatekeeper residue of EGFR, T790M (Kobayashi et al., 2005; Pao et al., 2005).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Pao et al., 2005
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BackgroundEML4-ALK Mutations in Lung Cancer That Confer Resistance to ALK Inhibitors
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“Unlike CML and GIST, in which the gatekeeper mutation is found in 20–25% of patients with acquired resistance to imatinib, the T790M mutation in EGFR is found in 50% of EGFR -mutant tumours with acquired resistance to erlotinib or gefitini”
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“Gefitinib Selective EGFR inhibitor (ATP competitive) EGFR T790M mutation [32,33]; Gene amplification (e.”
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“Patients who responded to gefitinib and subsequently relapsed were found to have T790M secondary mutations, also in exon 20 [19,20].”
BackgroundTargeting the cancer kinome through polypharmacology
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“…at the gatekeeper residues of the kinase domain which disables drug binding (Gorre et al., 2001; Blencke et al., 2003; Kobayashi et al., 2005; Pao et al., 2005; Soverini et al., 2005; Balak et al., 2006; Jabbour et al., 2006, 2008; Nicolini et al., 2006; Apperley, 2007; Costa et al., 2007;…”
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“Testing for the T790M mutation was then performed using standard methodologies (12, 23).”
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“second site EGFR point mutation that results in the substitution of threonine with methionine at amino acid position 790 (T790M;(7-10)).”
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Self-citationA Novel ALK Secondary Mutation and EGFR Signaling Cause Resistance to ALK Kinase Inhibitors
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“Recently, it has been reported by two groups that a secondary threonine-to-methionine mutation at codon 790 (T790M) of the EGFR gene is related to the acquired resistance to gefitinib and erlotinib (9, 10).”
BackgroundResultInfluential
- Authors
- Pao, W., Miller, V. A., Politi, K. A., Riely, G. J., Somwar, R., Zakowski, M. F., Kris, M. G., & Varmus, H.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Pao, William
- ORCID
- Venue
- PLoS Medicine
- Publisher
- Public Library of Science (PLoS)
- Published
- 2005-02-22
- Volume
- 2
- Issue
- 3
- Pages
- e73
- ISSN
- 1549-1277 (ISSN-L)
- 1549-1676
- PMC
- PMC549606
- OpenAlex
- W2002937040
- Cited by
- 3,527
- References
- 28
- Citations by year
- 2026: 45 · 2025: 61 · 2024: 59 · 2023: 139 · 2022: 104 · 2021: 116 · 2020: 140 · 2019: 154 · 2018: 203 · 2017: 221 · 2016: 232 · 2015: 255 · 2014: 246 · 2013: 272 · 2012: 222
- FWCI
- 134.24
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Medicine (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- American Cancer Society
- CHEST Foundation
- LUNGevity Foundation
- AstraZeneca
- Memorial Sloan-Kettering Cancer Center
- Washington University in St. Louis
- National Institutes of Health
- Genentech
- Canadian Institutes of Health Research
- National Cancer Institute (T 32 CA09207, T32CA009207)
- 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
- lung adenocarcinoma, gefitinib, erlotinib, acquired drug resistance, EGFR mutation, T790M mutation, EGFR kinase domain, tyrosine kinase inhibitors, KRAS mutation, imatinib resistance
- MeSH terms
- Erlotinib Hydrochloride, Gefitinib, Adenocarcinoma, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, DNA Mutational Analysis, Exons, Female, Humans, Lung Neoplasms, Middle Aged, Quinazolines, Tumor Cells, Cultured, Point Mutation, Disease Progression, Drug Resistance, Neoplasm, Reverse Transcriptase Polymerase Chain Reaction, ErbB Receptors
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