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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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“In EGFR kinase, structural and biochemical studies have shown the mechanism is more complex (Yun et al. 2008).”
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“Acquired resistance mutations such as those at the T790M gatekeeper residue increase the affinity of the mutant enzyme for ATP and further tip the balance of early generation EGFR inhibitors in favor of blocking wild-type over mutant oncogenic EGFR function [122].”
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“Mechanisms of acquired resistance include selection for the T790M mutation, which increases affinity of the receptor for ATP (7, 8) and amplification of the MET receptor tyrosine kinase (9, 10).”
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“As is shown by the structural research for bosutinib, the quinoline nitrogen interacts with methionine in ABL kinase [194], while similar interactions with methionine in EGFR have been observed in neratinib [195,196].”
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“The R1275Qmutation in ALK resembles oncogenic EGFR mutations found in NSCLC, such as L834R (L858R in proEGFR), increasing both kcat and Km, ATP (36, 37).”
BackgroundResisting Resistance: Targeted Therapies in Lung Cancer
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“Interestingly, the T790M substitution appears to render resistance primarily by enhancing the kinase affinity for ATP rather than by causing steric hindrance [36].”
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Amplification of EGFR T790M causes resistance to an irreversible EGFR inhibitor
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InfluentialEGFR T790M Mutation: A Double Role in Lung Cancer Cell Survival?
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BackgroundInfluentialSelf-citationMechanisms of Acquired Resistance to AZD9291
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“Approximately 60% of patients who had acquired resistance to EGFR TKIs harbored the gatekeeper EGFR mutation(12) that causes a steric hindrance(6) and increases the binding affinity of EGFR for adenosine triphosphate (ATP).(13) Although second-generation irreversible EGFR TKIs such as afatinib or dacomitinib show in v…”
BackgroundMolecular pathways and therapeutic targets in lung cancer
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“The T790M mutation affects the gatekeeper residue in the catalytic-kinase domain and confers drug resistance by increasing EGFR’s affinity for ATP – thus reducing the potency of the ATP-competitive kinase inhibitors [39].”
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“At the core of future research will be the need to determine the appropriate sequencing of treatments for patients with advanced EGFRm positive NSCLC along with standard EGFRTKIs and, as the disease landscape evolves, with use of later-generation EGFR-TKIs in the first-line setting, such as osimertinib.”
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“We next sought to determine the effect of the T790M mutation in EGFR on the velocity of covalent bond formation of an irreversible inhibitor in the ATP-binding pocket.”
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“hindrance imposed by the methionine residue, the T790M mutation has also been shown in direct binding assays to increase adenosine triphosphate affinity.(74)”
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BackgroundRedox Regulation of Epidermal Growth Factor Receptor Signaling through Cysteine Oxidation
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“The T790M mutation is located in the catalytic ATP-binding domain, and is thought to cause resistance to the TKIs by increasing the binding affinity of EGFR to ATP, thus decreasing TKI binding.(40) Based on these findings, it was speculated that agents which bind irreversibly to EGFR would overcome resistance to gefit…”
BackgroundProgress with covalent small-molecule kinase inhibitors
Zhao, Z., & Bourne, P. E. (2018) · Drug Discovery Today · doi:10.1016/j.drudis.2018.01.035 · Cited by 203
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“The substitution of threonine for methionine at position 790 increases the affinity of adenosine triphosphate (ATP), which is the main mechanism of formation of drug resistance [66].”
BackgroundFatty acid synthase mediates EGFR palmitoylation in EGFR mutated non‐small cell lung cancer
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“Importantly, DNA analyses from PC-9GR ruled out the link between the development of acquired resistance to Gefitinib of PC-9GR cells and secondary EGFR T790M mutation, which is the most common mechanisms of acquired TKI resistance in NSCLC (Yun et al, 2008; Sequist et al, 2011).”
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CH7233163 Overcomes Osimertinib-Resistant EGFR-Del19/T790M/C797S Mutation
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“Stabilization of the active conformation, the different mode of EGFR deregulation and the usually secondary occurrence of KI resistance mutations following primary mutations in the same cell might all explain why EGFR-T790 M gatekeeper mutation only mildly affects gefitinib binding, but restores the often reduced ATP…”
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Molecular Epidemiology of the Main Druggable Genetic Alterations in Non-Small Cell Lung Cancer
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“Globally, these two types of mutations are termed “classic” or “common” EGFR mutations, and they are thought to produce similar configurational changes within the ATP binding cleft of the protein [16].”
BackgroundInfluentialEffects of oncogenic mutations on the conformational free-energy landscape of EGFR kinase
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BackgroundTargeted covalent drugs of the kinase family
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“Coincidentally, EGFR T790M also enhances the affinity between ATP and its binding pocket(24), thereby synergistically conferring resistance to EGFR-TKIs.”
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“FRIN-3 also lost potency against EGFR, suggesting that covalence is required to achieve potency against EGFR, as is consistent with reports for other covalent inhibitors such as WZ4002 (4, 46).”
ResultSelf-citationThe EGFR T790M Mutation in Acquired Resistance to an Irreversible Second-Generation EGFR Inhibitor
Kim, Y.-W., Ko, J., Cui, Z.-Y., Abolhoda, A., Ahn, J. S., Ou, S.-H., Ahn, M., & Park, K. (2012) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-11-0750 · Cited by 179
“Efforts to block signaling from the compound mutant EGFR with small-molecule inhibitors has led to the conceptual introduction of experimental, irreversible EGFRTKIs that function primarily by covalently attaching to the cysteinyl-797 residue in the pocket of the EGFR-kinase domain (11).”
BackgroundResultInfluentialThe Underappreciated Role of Allostery in the Cellular Network
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Ins and Outs of Kinase DFG Motifs
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Effects of Erlotinib in EGFR Mutated Non-Small Cell Lung Cancers with Resistance to Gefitinib
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“Such a result is analogous to other forms of drug resistance, in which moving from complete to only partial kinase blockade is enough to allow tumor escape (3, 39).”
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“A prominent genetic mechanism is the acquisition of a secondary missense mutation, EGFR T790M, affecting the so-called ‘gatekeeper’ r esidue of the catalytic domain, leading to increased affinity of the mutant kinase for ATP [6].”
BackgroundTherapeutic targeting of epidermal growth factor receptor in human cancer: successes and limitations
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“For example, irreversible tyrosine kinase inhibitors may overcome the resistance to reversible inhibitors”
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“Examples of covalent inhibitors including their protein target(s) with active-site nucleophile: (A) aspirin; (B) neratinib; (C) rivastigmine; (D) Crystal structure of EGFR kinase domain in complex with neratinib, showing the covalent bond between the receptor and the ligand [27].”
BackgroundHsp90 Inhibition Suppresses Mutant EGFR-T790M Signaling and Overcomes Kinase Inhibitor Resistance
Shimamura, T., Li, D., Ji, H., Haringsma, H. J., Liniker, E., Borgman, C. L., Lowell, A. M., Minami, Y., McNamara, K. L., Perera, S. A., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-5428 · Cited by 153
“bind gefitinib with low nanomolar affinity, but restores wild-type affinity for ATP, diminishing the effectiveness of TKIs that must compete with ATP for receptor binding (10).”
Self-citationGatekeeper Mutations Mediate Resistance to BRAF-Targeted Therapies
Whittaker, S. R., Kirk, R., Hayward, R., Zambon, A., Virós, A., Cantariño, N., Affolter, A., Nourry, A., Niculescu‐Duvaz, D., Springer, C. J., et al. (2010) · Science Translational Medicine · doi:10.1126/scitranslmed.3000758 · Cited by 158
“However, the lack of clinical activity of sorafenib in melanoma (30) suggests that sorafenib is unable to inhibit BRAF in vivo through this mechanism either.”
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Self-citationProtein kinase biochemistry and drug discovery
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“This mutation increases the affinity of the kinase for ATP, and thus reduces the inhibitor efficacy [15–17].”
BackgroundGallo, L. H., Nelson, K. N., Meyer, A. N., & Donoghue, D. J. (2015) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2015.03.003 · Cited by 155
“T790M in EGFR in 50% of erlotinib- and gefitinib-resistant tumors [82,83] and T315I mutation in BCR-ABL in imatinib-resistant Chronic Myelogenous Leukemia (CML) [84,85].”
BackgroundIntratumoral Heterogeneity: From Diversity Comes Resistance
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“For example, mutation of a critical threonine residue of EGFR renders this protein insensitive to ATP-competitive inhibitors, and thus the oncogene remains active in the presence of drug (3).”
BackgroundMolecular-Targeted Therapies for Epidermal Growth Factor Receptor and Its Resistance Mechanisms
Yamaoka, T., Ohba, M., & Ohmori, T. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18112420 · Cited by 156
“For the T790M mutation, first-generation EGFR TKI binding affinity decreases to the same level as ATP because threonine at the ATP binding pocket is substituted by a larger molecule, methionine [88].”
BackgroundHata, A., Katakami, N., Yoshioka, H., Kaji, R., Masago, K., Fujita, S., Imai, Y., Nishiyama, A., Ishida, T., Nishimura, Y., et al. (2015) · Journal of Thoracic Oncology · doi:10.1097/jto.0000000000000647 · Cited by 150
“in ATP binding pocket.(17) T790M was initially considered as a secondary mutation following progression on EGFR-TKI therapy, but several recent reports suggested that T790M actually existed at a low frequency before EGFR-TKI therapy.”
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“The T790M mutation decreases the binding of the ATP-competitive, reversible EGFR-TKIs, such as gefitinib and erlotinib [15].”
Equally Potent Inhibition of c-Src and Abl by Compounds that Recognize Inactive Kinase Conformations
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“The pyridine and pyrimidine moieties (rings B and C) bind to the site normally occupied by the adenine group of ATP (Fig.”
InfluentialPersonalized therapy for lung cancer: striking a moving target
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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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