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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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Citations
Cites
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EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy
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“PCR products were ligated into plasmids using the TOPO TA-cloning kit (Invitrogen, Carlsbad, California, United States), as per manufacturer’s instructions.”
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“PCR products were ligated into plasmids using the TOPO TA-cloning kit (Invitrogen, Carlsbad, California, United States), as per manufacturer’s instructions.”
BackgroundMethodInfluentialSelf-citationClinical Resistance to STI-571 Cancer Therapy Caused by BCR-ABL Gene Mutation or Amplification
Gorre, M. E., Mohammed, M., Ellwood, K., Hsu, N., Paquette, R., Rao, P. N., & Sawyers, C. L. (2001) · Science · doi:10.1126/science.1062538 · Cited by 3,104 · cited 3×
“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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Overriding Imatinib Resistance with a Novel ABL Kinase Inhibitor
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“These results differ from those of acquired resistance mutation in CML [10], GIST [15,27], and HES [16].”
BackgroundResultInfluentialShah, N. P., Nicoll, J. M., Nagar, B., Gorre, M. E., PAQUETTE, R. L., Kuriyan, J., & Sawyers, C. L. (2002) · Cancer Cell · doi:10.1016/s1535-6108(02)00096-x · Cited by 1,614 · cited 3×
“It is also possible that EGFR amplification itself plays a role in acquired resistance, since imatinib-resistant clones have been shown to lack resistance mutations but contain amplified copies of BCR-ABL [11,28].”
BackgroundGefitinib-Sensitizing EGFR Mutations in Lung Cancer Activate Anti-Apoptotic Pathways
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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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- Krug, 2001, Proc Am Soc Clin Oncol, 20, 1328
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“Early experiments suggested that the T790M mutation sterically hindered the binding of TKIs to the EGFR kinase domain (Kobayashi et al. 2005; Pao et al. 2005).”
BackgroundCRIPTO1 expression in EGFR-mutant NSCLC elicits intrinsic EGFR-inhibitor resistance
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“In contrast, the T790M resistance mutation of EGFR (Pao et al., 2005; Kobayashi et al., 2005a) led to complete resistance to erlotinib when co-introduced with L858R (Figure 1b), thus validating the overall approach.”
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“The occurrence of amino acid substitutions has been described as a common form of resistance for cancer drugs, such as tyrosine kinase inhibitors, including imatinib, gefitinib, and erlotinib (Shah et al., 2002; Kobayashi et al., 2005; Pao et al., 2005).”
BackgroundImproved targeting of JAK2 leads to increased therapeutic efficacy in myeloproliferative neoplasms
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“The most common EGFR mutation associated with treatment resistance is due to the occurrence of a secondary mutation in the EGFR kinase domain [1, 2].”
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“Previous studies reported the association between the EGFR T790M mutation and acquired resistance to gefitinib in patients [13].”
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“A secondary point mutation in exon 20 of EGFR that substitutesmethionine for threonine at aminoacid position 790 (T790M) was identified in patients with NSCLC who developed acquired resistance to gefitinib or erlotinib (3, 4).”
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“H1975 cells harbor a wellcharacterized mutation of the EGFR receptor that interferes with the binding of gefitinib [24].”
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“Two genetically conferred mechanisms – T790M second mutation in EGFR (4-5), and the MET gene amplification (6) have been well reported to induce acquired resistance to EGFRTKIs in EGFR mutant lung cancer.”
EGFR-T790M Is a Rare Lung Cancer Susceptibility Allele with Enhanced Kinase Activity
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“Furthermore, the NCI-H1975 BAC cell line, which has never undergone tyrosine kinase inhibitor treatment, has both activating L858R and resistant T790M mutations, suggestive that T790M may be growth promoting ( 5 ).”
BackgroundUse of molecular markers for predicting therapy response in cancer patients
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“The T790M mutation allowed the phosphorylated substrate to escape from the binding pocket more quickly [159].”
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BackgroundCurcumin: Updated Molecular Mechanisms and Intervention Targets in Human Lung Cancer
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“In NSCLC, EGFRT790M is usually found on the same allele as the initial TKI-sensitizing EGFR mutation (30), suggesting that the two ERBB2 mutations may also occur in cis.”
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“2, Table 1) occurs at the conserved gatekeeper site within the kinase domain and is analogous to mutations that are commonly found in patients with acquired resistance to EGFR inhibitors in mutated EGFR–driven lung cancer (that is, the T790M substitution) (20) or to c-Abl tyrosine kinase inhibitors in BCRABL–driven ch…”
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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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