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The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP
Open accessAbstract
Lung cancers caused by activating mutations in the epidermal growth factor receptor (EGFR) are initially responsive to small molecule tyrosine kinase inhibitors (TKIs), but the efficacy of these agents is often limited because of the emergence of drug resistance conferred by a second mutation, T790M. Threonine 790 is the “gatekeeper” residue, an important determinant of inhibitor specificity in the ATP binding pocket. The T790M mutation has been thought to cause resistance by sterically blocking binding of TKIs such as gefitinib and erlotinib, but this explanation is difficult to reconcile with the fact that it remains sensitive to structurally similar irreversible inhibitors. Here, we show by using a direct binding assay that T790M mutants retain low-nanomolar affinity for gefitinib. Furthermore, we show that the T790M mutation activates WT EGFR and that introduction of the T790M mutation increases the ATP affinity of the oncogenic L858R mutant by more than an order of magnitude. The increased ATP affinity is the primary mechanism by which the T790M mutation confers drug resistance. Crystallographic analysis of the T790M mutant shows how it can adapt to accommodate tight binding of diverse inhibitors, including the irreversible inhibitor HKI-272, and also suggests a structural mechanism for catalytic activation. We conclude that the T790M mutation is a “generic” resistance mutation that will reduce the potency of any ATP-competitive kinase inhibitor and that irreversible inhibitors overcome this resistance simply through covalent binding, not as a result of an alternative binding mode.
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“The T790M mutation is believed to render the receptor refractory to inhibition by these reversible EGFR TKIs through exerting effects on both steric hindrance (22) and increased ATP affinity (23).”
From AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer (2014) · cites this paper as [23]
In the citing paper
“The EGFR-T790M mutation confers resistance by reversing the sensitization conferred by primary activating mutations, but it does so by altering the gatekeeper residue in the ATP-site that is known to be an important determinant of inhibitor specificity 50,57.”
From Structural, Biochemical, and Clinical Characterization of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer (2013) · cites this paper as [57]
In the citing paper
“This mutation, leads to an increase in ATP affinity, thus making it more difficult for reversible EGFR TKIs gefitinib and erlotinib to bind the EGFR TKI domain (11).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [11]
In the citing paper
“Covalent binding is required to overcome the increased ATP affinity mediated by T790M (11).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [11]
In the citing paper
“The presence of the T790M variant reduces binding of first-generation or second-generation EGFR-TKIs to the ATP-binding pocket of EGFR, thereby reducing EGFR-TKI–mediated inhibition of downstream signaling and potentially leading to disease progression.17–19”
From Osimertinib or Platinum–Pemetrexed in EGFR T790M–Positive Lung Cancer (2017) · cites this paper as [17]
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InfluentialCrystal structure of EGFR T790M/C797S/V948R in complex with EAI045
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“…is the gatekeeper residue in the EGF receptor and the methionine substitution introduces a bulky amino acid side chain, resulting in a steric hindrance that may interfere with the binding of gefitinib or erlotinib to the EGF receptor (Kobayashi et al., 2005; Kwak et al., 2005; Yun et al., 2008).”
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“proposed that the resistance in T790M mutation causes drug resistance by restoring affinity for ATP (Azam et al., 2008; Suda et al., 2009; Yun et al., 2008; Zhou et al., 2009), thus, leading to the hypothesis that T790M mutation in EGFR kinase increases the affinity for ATP by extrastabilization of hydrophobic spine.”
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“Tyrosine kinase inhibitors in general compete with ATP to bind to the kinase domain of EGFR, and EGFR T790M significantly increases the affinity of EGFR for ATP, thereby reducing the efficacy of first-generation EGFR TKIs [30].”
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“Acquisition of a secondary T790M mutation in addition to an underlying L858R mutation was shown to enhance the affinity of the EGFR kinase for ATP such that the binding of ATP-competitive first-generation reversible TKIs occurs less readily.(23) Patients with the T790M mutation have a median post-progression survival…”
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“This substitution increases the receptor’s affinity for adenosine triphosphate and impairs receptor-drug binding by inhibiting hydrogen bond formation or inducing steric hindrance.(2,4) This T790M resistant mutation was found in approximately 60% of rebiopsy samples obtained from patients with acquired resistance to E…”
BackgroundA Decade of Advances in Treatment for Advanced Non–Small Cell Lung Cancer
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“It was initially thought that the T790M mutation led to resistance simply by steric interference with drug binding in the adenosine triphosphate (ATP) pocket of EGFR; however, subsequent studies suggest that the introduction of this mutation leads to increased ATP affinity of the mutant EGFR receptor.(70,71) Because e…”
BackgroundKhaddour, K., Jonna, S., Deneka, A. Y., Patel, J. D., Abazeed, M. E., Golemis, E. A., Borghaei, H., & Boumber, Y. (2021) · Cancers · doi:10.3390/cancers13133164 · Cited by 67
“This mutation increases ATP affinity at the binding pocket of the receptor and prevents first- and second-generation EGFR TKIs from binding to the ATP region [50].”
BackgroundRecent advances in the development of EGFR degraders: PROTACs and LYTACs
Hong, D., Zhou, B., Zhang, B., Ren, H., Zhu, L., Zheng, G., Ge, M., & Ge, J. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.114533 · Cited by 67
Haan, C., Behrmann, I., & Haan, S. (2010) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2010.01018.x · Cited by 64
“Furthermore, it was postulated that this mutation to a bulkier residue may increase the stability of the ‘hydrophobic spine’, a stack of hydrophobic residues that forms upon activation of protein kinases [148, 149].”
BackgroundHembrough, T., Thyparambil, S. P., Liao, W.-L., Darfler, M. M., Abdo, J., Bengali, K. M., Hewitt, S. M., Bender, R. A., Krizman, D. B., & Burrows, J. (2013) · Journal of Molecular Diagnostics · doi:10.1016/j.jmoldx.2013.03.002 · Cited by 63
“In most cases, resistance is driven by alterations in the expression of alternate signaling pathways, not through changes in the drug target, although secondary mutations in EGFR have been described.(10) Diagnostic testing is essential for identifying the subset of patients with cancer who are best suited for targeted…”
Wang, Z., Wu, X., Liang, Y.-N., Wang, L., Song, Z., Liu, J., & Tang, Z. (2016) · Molecules · doi:10.3390/molecules21101267 · Cited by 64
Sullivan, I., & Planchard, D. (2016) · Therapeutic Advances in Respiratory Disease · doi:10.1177/1753465816670498 · Cited by 65
Drugging the catalytically inactive state of RET kinase in RET-rearranged tumors
Plenker, D., Riedel, M., Brägelmann, J., Dammert, M. A., Chauhan, R., Knowles, P. P., Lorenz, C., Keul, M., Bührmann, M., Pagel, O., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aah6144 · Cited by 64
Distinct Patterns of Acral Melanoma Based on Site and Relative Sun Exposure
Haugh, A. M., Zhang, B., Quan, V. L., Garfield, E. M., Bubley, J. A., Kudalkar, E. M., Verzì, A. E., Walton, K. E., VandenBoom, T. G., Merkel, E. A., et al. (2017) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2017.08.022 · Cited by 63
“…found in a volar melanoma, leads to acquired resistance to M AN US CR IP T AC CE PT ED 11 tyrosine kinase inhibitors by enhancing receptor ATP affinity in lung cancer but has also been shown to cause tumorigenesis as a de novo mutation (Liu et al., 2017, Mohammed et al., 2017, Yun et al., 2008).”
BackgroundChen, Q., Pan, Z., Zhao, M., Wang, Q., Qiao, C., Miao, L., & Ding, X. (2017) · Journal of Cellular Physiology · doi:10.1002/jcp.26351 · Cited by 62
“This mutation, which occurs in the original drug-sensitive EGFR mutation, either from steric hindrance or reduced affinity of the kinase domain for the EGFR-TKI influences EGFR-TKI effectiveness (Yun et al., 2008).”
BackgroundTomasello, C., Baldessari, C., Napolitano, M., Orsi, G., Grizzi, G., Bertolini, F., Barbieri, F., & Cascinu, S. (2018) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2018.01.013 · Cited by 65
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Acquired Resistance to Clinical Cancer Therapy: A Twist in Physiological Signaling
WICKI, A. N., Mandalà, M., Massi, D., Taverna, D., Tang, H., Hemmings, B. A., & Xue, G. (2016) · Physiological Reviews · doi:10.1152/physrev.00024.2015 · Cited by 64
“Although it is not fully understood mechanistically, studies from structural biology predict that the T790M mutation mediates steric hindrance in the ATP-binding pocket to limit the access of small molecular inhibitors (134) and increases ATP-binding affinity in the kinase domain of EGFR (332).”
BackgroundMolecular modelling and simulations in cancer research
Friedman, R., Boye, K., & Flatmark, K. (2013) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2013.02.001 · Cited by 66
“However, subsequent studies revealed that the T790M mutant confers resistance by a higher binding affinity for ATP [59], a mechanism that could be overcome by irreversible EGFR inhibitors.”
BackgroundTartarone, A., Lazzari, C., Lerose, R., Conteduca, V., Improta, G., Zupa, A., Bulotta, A., Aieta, M., & Gregorc, V. (2013) · Lung Cancer · doi:10.1016/j.lungcan.2013.05.020 · Cited by 63
“The presence of T790M, altering the conformation of the TK domain of the EGFR, restores the affinity of the receptor for the ATP thus reducing the ability of reversible TKIs to effectively compete with ATP [33–35].”
BackgroundChoe, C., Shin, Y.-S., Choi, S., Lee, J., Kim, S. Y., Cho, Y. B., Kim, J., & Kim, C. (2015) · OncoTargets and Therapy · doi:10.2147/ott.s89659 · Cited by 64
“It has been proposed that lung cancers with mutated EGFR are dependent on the EGFR pathway and these inhibitors have a stronger binding affinity for mutant than wild-type EGFR, leading to good results in many patients.(17) Invariably, however, most patients develop resistance to EGFR TKI therapy and lung cancer with h…”
BackgroundTani, T., Yasuda, H., Hamamoto, J., Kuroda, A., Arai, D., Ishioka, K., Ohgino, K., Miyawaki, M., Kawada, I., Naoki, K., et al. (2015) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-15-0084 · Cited by 65
“TheEML4-ALK L1196MandEGFRT790Mmutations are called "gatekeeper" mutations, because of the key location of the encoded amino acid substitutions at the entrance to a hydrophobic pocket at the back of the ATP binding cleft (26).”
BackgroundMAP4K4 is a novel MAPK/ERK pathway regulator required for lung adenocarcinoma maintenance
Gao, X., Chen, G., Gao, C., Zhang, D. H., Kuan, S., Stabile, L. P., Liu, G., & Hu, J. (2017) · Molecular Oncology · doi:10.1002/1878-0261.12055 · Cited by 62
“The most common mechanism for acquired resistance to EGFR inhibitors such as erlotinib is the mutation of threonine 790 to a methionine (T790M) in the kinase domain of the EGFR gene, which results in increased kinase affinity for ATP, thus decreasing the sensitivity to ATP-competitive inhibitors (Yun et al., 2008).”
BackgroundBagchi, A., Haidar, J. N., Eastman, S. W., Vieth, M., Topper, M., Iacolina, M. D., Walker, J. M., Forest, A., Shen, Y., Novosiadly, R. D., et al. (2018) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-17-0575 · Cited by 60
“An appreciation for the molecular mechanism of T790M-acquired resistance (19) led to the development of third-generation inhibitors that can circumvent this resistance mechanism (20).”
BackgroundInterocular induction of illusory size perception
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Epidermal Growth Factor Receptor (EGFR) Signaling and Covalent EGFR Inhibition in Lung Cancer
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“Yun CH, Mengwasser KE, Toms AV, et al: The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP.”
BackgroundBisphosphonates inactivate human EGFRs to exert antitumor actions
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The Role of EGFR Inhibition in the Treatment of Non-Small Cell Lung Cancer
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Polo-Like Kinase 4’s Critical Role in Cancer Development and Strategies for Plk4-Targeted Therapy
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“[50] 112 EGFR mutants MD & Clinical data of 942 patients Binding energies [56] EGFR ErbB-3 hetrodimers Hydrogen bonds Stability analysis [57] 30 EGFR mutants Interaction footptint matrix and PCA EGFR-TKI sensitivity prediction [58] WT, L858R, T790M computational methods Affinity for Gefitinib and ATP [59] WT & T854A M…”
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Targeting Gatekeeper Mutations for Kinase Drug Discovery
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The role of HGF/c-MET signaling pathway in lymphoma
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“For example, c-MET amplification or activation has been reported as one of the major mechanisms for developing resistance to EGFR tyrosine kinase inhibitor (TKI) treatment in non-small cell lung cancer (NSCLC) patients [8, 12, 13].”
BackgroundFBXL2 counteracts Grp94 to destabilize EGFR and inhibit EGFR-driven NSCLC growth
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Irreversible Inhibition of Epidermal Growth Factor Receptor Activity by 3-Aminopropanamides
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Metadata
- Authors
- Yun, C.-H., Mengwasser, K. E., Toms, A. V., Woo, M. S., Greulich, H., Wong, K.-K., Meyerson, M., & Eck, M. J.
- Affiliations
- Dana-Farber Cancer Institute (US)
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Eck, Michael J.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2008-02-12
- Volume
- 105
- Issue
- 6
- Pages
- 2070-2075
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2538882
- OpenAlex
- W2159013299
- Cited by
- 2,118
- References
- 42
- Citations by year
- 2026: 101 · 2025: 125 · 2024: 94 · 2023: 141 · 2022: 132 · 2021: 138 · 2020: 107 · 2019: 111 · 2018: 144 · 2017: 142 · 2016: 139 · 2015: 143 · 2014: 112 · 2013: 121 · 2012: 115
- FWCI
- 79.66
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- Leukemia and Lymphoma Society
- National Institutes of Health
- Novartis Institutes for BioMedical Research
- National Cancer Institute (R01CA116020, CA 116020, R01CA080942, CA080942)
- 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 › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- T790M mutation, EGFR, drug resistance, tyrosine kinase inhibitors, gefitinib, erlotinib, ATP affinity, gatekeeper residue, L858R mutation, irreversible inhibitors, covalent binding, kinase activation, lung cancer, ATP-competitive inhibitors
- MeSH terms
- Gefitinib, Adenosine Triphosphate, Animals, Drug Resistance, Enzyme Inhibitors, Insecta, Kinetics, Mutation, Protein Conformation, Quinazolines, Crystallography, X-Ray, ErbB Receptors
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