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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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In the citing paper
“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
Paez, J. G., Jänne, P. A., Lee, J. C., Tracy, S., Greulich, H., Gabriel, S., Herman, P., Kaye, F. J., Lindeman, N., Boggon, T. J., et al. (2004) · Science · doi:10.1126/science.1099314 · Cited by 9,368 · cited 13×
“PCR products were ligated into plasmids using the TOPO TA-cloning kit (Invitrogen, Carlsbad, California, United States), as per manufacturer’s instructions.”
BackgroundInfluentialPao, W., Miller, V., Zakowski, M., Doherty, J., Politi, K., Sarkaria, I., Singh, B., Heelan, R., Rusch, V., Fulton, L., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0405220101 · Cited by 4,338 · cited 17×
“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].”
BackgroundResultShigematsu, H., Lin, L., Takahashi, T., Nomura, M., Suzuki, M., Wistuba, I. I., Fong, K. M., Lee, H., Toyooka, S., Shimizu, N., et al. (2005) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/dji055 · Cited by 2,377
Overriding Imatinib Resistance with a Novel ABL Kinase Inhibitor
Shah, N. P., Tran, C., Lee, F. Y., Chen, P., Norris, D. J., & Sawyers, C. L. (2004) · Science · doi:10.1126/science.1099480 · Cited by 1,804 · cited 2×
“The new drugs bind to ABL in an ‘‘open’’ conformation, as opposed to imatinib, which binds ABL in a ‘‘closed’’ conformation [12,13].”
BackgroundCools, J., DeAngelo, D. J., Gotlib, J. R., Stover, E. H., Legare, R. D., Cortes, J. E., Kutok, J. L., Clark, J., Galinsky, I. A., Griffin, J. D., et al. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa025217 · Cited by 1,714 · cited 5×
“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
Sordella, R., Bell, D. W., Haber, D. A., & Settleman, J. E. (2004) · Science · doi:10.1126/science.1101637 · Cited by 1,605 · cited 3×
“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.”
BackgroundResultStamos, J. L., Sliwkowski, M. X., & Eigenbrot, C. W. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m207135200 · Cited by 1,594 · cited 1×
“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 [”
BackgroundKRAS Mutations and Primary Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib
Pao, W. J., Wang, T. Y., Riely, G. J., Miller, V. A., Pan, Q., Ladanyi, M., Zakowski, M. F., Heelan, R. T., Kris, M. G., & VARMUS, H. E. (2005) · PLoS Medicine · doi:10.1371/journal.pmed.0020017 · Cited by 1,517 · cited 7×
“To determine whether the 2369 CfiT mutation was a previously overlooked EGFR mutation found in NSCLCs, we re-reviewed exon 20 sequence tracings derived from analysis of 96 fresh-frozen resected tumors [3] and 59 paraffinembedded tumors [7], all of which were removed from patients prior to treatment with an EGFR tyrosi…”
BackgroundMethodInfluentialSelf-citationThe development of imatinib as a therapeutic agent for chronic myeloid leukemia
Deininger, M. W., Buchdunger, E., & Druker, B. J. (2004) · Blood · doi:10.1182/blood-2004-08-3097 · Cited by 1,269
Mutations of the Epidermal Growth Factor Receptor Gene in Lung Cancer
Kosaka, T., Yatabe, Y., Endoh, H., Kuwano, H., Takahashi, T., & Mitsudomi, T. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-2818 · Cited by 1,220 · cited 3×
“We have not identified this mutation in 155 tumors (see above), and among nearly 1,300 lung cancers in which analysis of EGFR exons 18 to 21 has been performed [1,2,3,4,5,6], only one tumor (which also harbored an L858R mutation) was reported to contain the T790M mutation.”
BackgroundSawyers, C. L. (2004) · Nature · doi:10.1038/nature03095 · Cited by 1,198 · cited 1×
“Although imatinib inhibits different kinases in various diseases (BCR-ABL in CML, KIT or PDGFR-alpha in gastrointestinal stromal tumors [GISTs], and PDGFR-alpha in hypereosinophilic syndrome [HES]) (reviewed in [14]), some tumors that become refractory to treatment with imatinib appear to have analogous secondary muta…”
BackgroundA Unique Structure for Epidermal Growth Factor Receptor Bound to GW572016 (Lapatinib)
Wood, E. R., Truesdale, A. T., McDonald, O. B., Yuan, D. Y., Hassell, A. M., Dickerson, S. H., Ellis, B., Pennisi, C., Horne, E., Lackey, K. E., et al. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-1168 · Cited by 1,125 · cited 1×
“For example, the crystal structure of another EGFR inhibitor, lapatinib (GW572016), was recently solved bound to EGFR [26].”
BackgroundHuang, S.-F. K., Liu, H.-P., Li, L.-H., Ku, Y.-C., Fu, Y.-N., Tsai, H., Chen, Y.-T., Lin, Y., Chang, W.-C., Kuo, H.-P., et al. (2004) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-04-1245 · Cited by 545
Gefitinib Induces Apoptosis in the EGFRL858R Non–Small-Cell Lung Cancer Cell Line H3255
Tracy, S. I., Mukohara, T., Hansen, M., Meyerson, M. M., Johnson, B. E., & Janne, P. A. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-1905 · Cited by 372 · cited 1×
“As reported, H3255 contained an L858R mutation [19] and H1650 contained an exon 19 deletion [18].”
BackgroundChen, L. L., Trent, J. C., Wu, E. F., Fuller, G. N., Ramdas, L., Zhang, W., Raymond, A. K., Prieto, V. G., Oyedeji, C. O., Hunt, K. K., et al. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-0085 · Cited by 338 · cited 4×
“Abbreviations: CML, chronic myelogenous leukemia; CT, computed tomography; del, deletion; EGFR, epidermal growth factor receptor; GIST, gastrointestinal stromal tumor; HES, hypereosinophilic syndrome; NSCLC, non-small cell lung cancer; p-EGFR, phospho-EGFR; PCR-RFLP, PCR restriction fragment length polymorphism; SNP,…”
ResultInfluentialStrategies to overcome resistance to targeted protein kinase inhibitors
Daub, H., Specht, K., & Ullrich, A. (2004) · Nature Reviews Drug Discovery · doi:10.1038/nrd1579 · Cited by 337 · cited 2×
“By contrast, ATP would likely not depend on the accessibility of the same hydrophobic cavity and is therefore probably not affected by the incorporation of a bulky methionine side chain [25].”
BackgroundTamborini, E., Bonadiman, L., Greco, A., Albertini, V., Negri, T., Gronchi, A., Bertulli, R., Colecchia, M., Casali, P. G., Pierotti, M. A., et al. (2004) · Gastroenterology · doi:10.1053/j.gastro.2004.02.021 · Cited by 323 · cited 1×
“]. In GIST and HES, respectively, the analogous T670I mutation in KIT and T674I mutation in PDGFR-alpha have been associated with acquired resistance to this drug [”
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“[21] and a related quinazoline inhibitor, PD153035 [22].”
BackgroundBlencke, S., Ullrich, A., & Daub, H. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m211158200 · Cited by 117 · cited 2×
“[21] and a related quinazoline inhibitor, PD153035 [22].”
BackgroundMolecular mechanisms of resistance to STI571 in chronic myeloid leukemia
Gorre, M. E., & Sawyers, C. L. (2002) · Current Opinion in Hematology · doi:10.1097/00062752-200207000-00007 · Cited by 113
Al‐Ali, H. K., Heinrich, M. C., Lange, T., Krahl, R., Mueller, M., Müller, C., Niederwieser, D. W., Druker, B. J., & Deininger, M. W. (2004) · The Hematology Journal · doi:10.1038/sj.thj.6200319 · Cited by 111
Kreuzer, K. ‐., le Coutre, P., Landt, O., Na, I., Schwarz, M., Schultheis, K., Hochhaus, A., & Dörken, B. (2003) · Annals of Hematology · doi:10.1007/s00277-003-0644-y · Cited by 87 · cited 1×
“However, based upon analogous studies in CML, it is also possible that NSCLC subclones bearing this secondary mutation pre-exist within the primary tumor clone in individual patients, albeit at low frequency [23].”
BackgroundA rapid fluorometric assay to measure neuronal survival in vitro
Bozyczko‐Coyne, D., McKENNA, B., Connors, T. J., & Neff, N. T. (1993) · Journal of Neuroscience Methods · doi:10.1016/0165-0270(93)90009-g · Cited by 63 · cited 1×
“relative cell viability among cell lines [20].”
Kreuzer, K.-A., le Coutre, P., Landt, O., Na, I.-K., Schwarz, M., Schultheis, K., Hochhaus, A., & D�rken, B. (2003) · Annals of Hematology · doi:10.1007/s00277-003-0690-5 · Cited by 48
Flagged first, then by citations
Research works printed but not linked: 2
- Krug, 2001, Proc Am Soc Clin Oncol, 20, 1328
- Daub, 2004, Nat Rev Cancer, 3, 1001
Cited by
Sorted by citations
Travis, W. D., Brambilla, E. M., Noguchi, M., Nicholson, A. G., Geisinger, K. R., Yatabe, Y., Beer, D. G., Powell, C. A., Riely, G. J., Schil, P. E. V., et al. (2011) · Journal of Thoracic Oncology · doi:10.1097/jto.0b013e318206a221 · Cited by 4,834
Self-citationCancer drug resistance: an evolving paradigm
Holohan, C., Van Schaeybroeck, S., Longley, D. B., & Johnston, P. G. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3599 · Cited by 4,681
Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors
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“They have identified several resistance mechanisms, two of which—EGFR mutation T790M (6, 7) andMET amplification (8, 9)—have been validated in the clinic.”
BackgroundERBB receptors and cancer: the complexity of targeted inhibitors
Hynes, N. E., & Lane, H. A. (2005) · Nature reviews. Cancer · doi:10.1038/nrc1609 · Cited by 3,379
“The recent identification of additional mutations in NSCLC patients whose tumours displayed drug-sensitive mutations and who initially responded to TKI treatment might explain some of the acquired resistance to EGFR inhibitor”
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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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