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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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“H1975 cells harbor activating EGFR mutations [17]”
From Clathrin adapters AP-1 and GGA2 support expression of epidermal growth factor receptor for cell growth (2021) · cites this paper as [17]
In the citing paper
“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]
In the citing paper
“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 the citing paper
“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
In the citing paper
“Accordingly, cell growth was suppressed by the depletion of AP-1 in a non-cancer cell line, ARPE-19, and a NSCLC-derived cancer cell line, H1975, which harbors activating EGFR mutations [17].”
From Clathrin adapters AP-1 and GGA2 support expression of epidermal growth factor receptor for cell growth (2021) · cites this paper as [17]
In the citing paper
“H1975 cells harbor activating EGFR mutations [17], and as such, these results suggest the involvement of AP-1 in EGFR-dependent cell growth.”
From Clathrin adapters AP-1 and GGA2 support expression of epidermal growth factor receptor for cell growth (2021) · cites this paper as [17]
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BackgroundMethodInfluentialSelf-citationClinical Resistance to STI-571 Cancer Therapy Caused by BCR-ABL Gene Mutation or Amplification
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“For example, in CML, a commonly found mutation is a CfiT single nucleotide change that replaces threonine with isoleucine at position 315 (T315I) in the ABL kinase domain [9,10,11].”
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“These results differ from those of acquired resistance mutation in CML [10], GIST [15,27], and HES [16].”
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“This scenario could explain the seemingly contradictory report by others who found the H1975 cell line to be highly sensitive to gefitinib [18]; our H1975 cells could represent a subclone that emerged over time.”
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“From analysis of the crystal structure of the EGFR kinase domain bound to erlotinib, it is has been shown that the wild-type threonine residue at position 790 is located in the hydrophobic ATP-binding pocket of the catalytic region, where it forms a critical hydrogen bond with the drug [”
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“…of EGFR Status It is of particular interest that ROR1 knockdown inhibited the growth of NCI-H1975 cells, because this line carries double EGFR mutations L858R and T790M, the latter of which is a well-recognized mutation that confers resistance to EGFR TKI (Kobayashi et al., 2005; Pao et al., 2005).”
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“Although in some of these cases, an additional mutation in EGFR was identified that conferred resistance to the inhibitor, in the other cases no second mutation was identified, suggesting that other mechanisms of resistance exist (38, 39).”
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Metadata
- 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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