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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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“While these 4-anilinoquinazolines inhibit Abl too poorly to be effective in cells, where they must compete with high concentrations of ATP for binding to the kinase, other 4-anilinoquinazolines could prove effective against the T315I mutation. It is interesting to note that, during the treatment of cancers caused by d…”
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Meric‐Bernstam, F., & Mills, G. B. (2012) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2012.127 · Cited by 150
USP8 Is a Novel Target for Overcoming Gefitinib Resistance in Lung Cancer
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Phosphorylation of the ATP-binding loop directs oncogenicity of drug-resistant BCR-ABL mutants
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Epidermal Growth Factor Receptor Mutations in Patients with Non–Small Cell Lung Cancer
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“However, other irreversible EGFR inhibitors still retain inhibitory activity, suggesting that a further understanding of the structure/function relationship of mutated EGFR and EGFR inhibitors (23, 24).”
BackgroundCancer Genomics and Inherited Risk
Stadler, Z. K., Schrader, K. A., Vijai, J., Robson, M. E., & Offit, K. (2014) · Journal of Clinical Oncology · doi:10.1200/jco.2013.49.7271 · Cited by 149
Kinase and Histone Deacetylase Hybrid Inhibitors for Cancer Therapy
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“A well-characterized mechanism of resistance is the acquisition of the T790M mutation in exon 20 of the EGFR kinase domain (46, 47).”
BackgroundEffect of Sulindac and Erlotinib vs Placebo on Duodenal Neoplasia in Familial Adenomatous Polyposis
Samadder, N. J., Neklason, D. W., Boucher, K. M., Byrne, K. R., Kanth, P., Samowitz, W. S., Jones, D. A., Tavtigian, S. V., Done, M. W., Berry, T., et al. (2016) · JAMA · doi:10.1001/jama.2016.2522 · Cited by 145
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“75 The classification and treatment paradigm for NSCLC changed drastically in 2004 with 76 the discovery of the epidermal growth factor receptor (EGFR) mutations as a driver in NSCLC, 77 occurring in about 10-30% of patients (3,4).”
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Rational bases for the development of EGFR inhibitors for cancer treatment
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“The binding of erlotinib to the receptor also appears to be affected in some resistant patients: a mutation in exon 20 of EGFR (T790M) was recently discovered to affect the binding of erlotinib to the receptor and lower its efficacy.(15,22) In addition to these alterations directly affecting the EGFR pathway, deleteri…”
BackgroundTargeting EGFR and HER-2 receptor tyrosine kinases for cancer drug discovery and development
Kamath, S., & Buolamwini, J. K. (2006) · Medicinal Research Reviews · doi:10.1002/med.20070 · Cited by 145
Amit, I., Wides, R., & Yarden, Y. (2007) · Molecular Systems Biology · doi:10.1038/msb4100195 · Cited by 147
“For example, only one-third of HER2-overexpressing mammary tumors respond to trastuzumab (primary resistance), and patients who initially respond to mAbs or to TKIs often relapse due to evolvement of secondary resistance”
BackgroundPolymorphisms, Mutations, and Amplification of the EGFR Gene in Non-Small Cell Lung Cancers
Nomura, M., Shigematsu, H., Li, L., Suzuki, M., Takahashi, T., Estess, P., Siegelman, M. H., Feng, Z., Kato, H., Marchetti, A., et al. (2007) · PLoS Medicine · doi:10.1371/journal.pmed.0040125 · Cited by 143
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Existing and Emerging Technologies for Tumor Genomic Profiling
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Protein-structure-guided discovery of functional mutations across 19 cancer types
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“We found that EGFR with the p.Thr790Met variant was resistant to gefitinib, consistent with previous reports 26 .”
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Small-Cell Lung Cancers in Patients Who Never Smoked Cigarettes
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Structural Insight and Development of EGFR Tyrosine Kinase Inhibitors
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“Furthermore, the cell line with L858R/T790M mutation showed a 100-fold lower sensitivity to gefitinib and erlotinib, indicating the resistance of the drugs [76].”
BackgroundMolecular tumour boards — current and future considerations for precision oncology
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“NSCLC patients who initially respond to TKIs, but subsequently relapse, often have a secondary T790M mutation, which results in acquired drug resistance (Kobayashi et al., 2005; Pao et al., 2005).”
BackgroundTherapeutic Potential of Targeting the Oncogenic SHP2 Phosphatase
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Improving Cancer Treatment via Mathematical Modeling: Surmounting the Challenges Is Worth the Effort
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“On the other hand, a missense mutation in exon 20, especially T790M, showed gefitinib resistance, as previously reported (Kobayashi et al, 2005; Pao et al, 2005b).”
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“Tumors of most patients treated first-line with a currently approved EGFR-TKI develop resistance, however, leading to disease progression (Kobayashi et al., 2005; Pao et al., 2005; Sequist et al., 2011).”
BackgroundSelective and reversible modification of kinase cysteines with chlorofluoroacetamides
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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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