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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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Self-citationClinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms
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“The T790M mutation confers resistance by increasing the affinity of the EGFR for ATP relative to that for EGFR-TKIs [12].”
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“It is known to enhance the affinity of oncogenic forms of EGFR kinase to ATP[16], explaining its drug resistant properties despite retention of the ability to bind EGFR inhibitors.”
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“It is believed that the steric hindrance posed by methionine which affects hydrogen bonds formation between TKIs and tyrosine kinases is largely responsible for the inability of TKIs to bind to tyrosine kinases [147, 148]; some reports also depicts that acquired TKI resistance from T790M mutation and EGFR-sensitive mu…”
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“EGFR T790M mutation is known to increase the affinity of the receptor tyrosine kinase for adenosine triphosphate (ATP) and also sterically hinder the binding of EGFR to TKIs, thereby leading to the failure of TKI treatment [8, 9].”
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“Furthermore, methionine is a quite flexible residue which can facilitate inhibitor binding by a simple shift which was already observed in crystal structures of AEE788 and HKI-272 (Yun et al., 2008).”
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“The T790M mutation at the gatekeeper position of the ATP kinase pocket is capable of annulling the sensitization of activating mutations (16,28).”
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“Patients who became resistant to first generation EGFR TKIs often acquire a T790M somatic mutation, which has been designated a “gatekeeper” mutation (23) that increases affinity for ATP (24).”
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“Moreover, this substitution, located within the ATP binding pocket, results in a greater affinity of the EGFR for ATP, reducing the potency of ATP-competitive drugs [23].”
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Self-citationMorphine-Induced Epidermal Growth Factor Pathway Activation in Non–Small Cell Lung Cancer
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“This mutation increases the affinity of EGFR for ATP, thus reducing the potency of ATP-competitive TKIs [26].”
BackgroundMolecular Mechanisms and Targeted Therapies Including Immunotherapy for Non-Small Cell Lung Cancer
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A Novel Classification of Lung Cancer into Molecular Subtypes
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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 [23].”
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“Unfortunately, almost all patients with these activating mutations eventually develop acquired resistance while receiving EGFR-TKI treatment.3,4 A secondary mutation in exon 20 (T790M) is observed in approximately 50% of such cases.5,6 The T790M mutation alters the relative affinity of the mutant receptor in favor of…”
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Signaling cross-talk in the resistance to HER family receptor targeted therapy
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The Design of Covalent Allosteric Drugs
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Acquired resistance to targeted therapies in NSCLC: Updates and evolving insights
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“The T790M mutation spatially hinders the binding of the first and second-generation TKIs to the ATP -binding site of EGFR, causing the inability to inhibit its activity [11].”
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“For example a T790M mutation in the EGFR confers resistance to ATP-competitive kinase inhibitors such as gefitinib and erlotinib by increasing the ATP affinity of the EGFR by more than an order of magnitude (47).”
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“T790M mutation increases the kinase affinity for ATP, reducing the inhibitory efficacy of EGFR ATP-competitive inhibitors such as gefitinib and erlotinib [66, 67].”
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“The irreversible covalent binding of neratinib to Cys-797 of EGFR overcomes resistance to the gatekeeper EGFR T790M mutation, a common resistance mechanism to erlotinib or gefitinib in L858R-mutated lung cancer [62,63].”
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“Substitution with this bulky methionine residue had been suggested to cause resistance by sterically blocking binding of gefitinib or erlotinib [3, 4], but a more recent study indicated that the T790M mutation caused drug resistance by increasing the affinity for ATP [5].”
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“The H1975 human lung adenocarcinoma cell line with EGFR-L858R/T790M double mutation (20) was kindly provided by Dr.”
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New Electrophiles and Strategies for Mechanism-Based and Targeted Covalent Inhibitor Design
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The ABC of protein kinase conformations
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Epidermal Growth Factor Receptor (EGFR)-Mutated Non-Small-Cell Lung Cancer (NSCLC)
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“AURA3 recruited 419 patients with T790M mutation-positive NSCLC post progression on first-line EGFR TKIs.”
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Cancer driver mutations in protein kinase genes
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“cer driver [116–118] and ABL cancer driver mutants [119– 121] have also suggested that activation by EGFR T790M and ABL T315I mutations may be triggered by conserved interactions between Phe of the conserved DFG motif and the mutated gate-keeper residue, which may unlock the inactive kinase conformation and facilitate…”
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Targeted Therapies for Lung Cancer
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“EGFRT790M is reported to promote resistance by simultaneously increasing ATP affinity and decreasing drug binding (28).”
Epidermal growth factor receptor: Structure-function informing the design of anticancer therapeutics
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“The EGFR T790M mutation in particular has also been shown to decrease EGFR affinity for gefitinib in the context of L858R mutation via increased affinity for ATP.(48) Interestingly, rare germline mutations encoding EGFR T790M appear to cause inherited susceptibility to lung cancer, often accompanied by activating soma…”
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“The H1975 human lung adenocarcinoma cell line with EGFR-L858R/T790M double mutation (10) was kindly provided by Dr.”
BackgroundMethodSun, H., Li, Y., Tian, S., Wang, J., & Hou, T. (2014) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003729 · Cited by 100
“survive by means of activating other signaling pathways [12–16], regulating the expression level of the associated genes or gene products [17–19], or more directly, hindering the drugs binding [20,21], enhancing the substrates binding [22], or re-activating the target [23] with acquired secondary mutations in the drug…”
BackgroundResistance is futile: overcoming resistance to targeted therapies in lung adenocarcinoma
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“More recently, data demonstrating that gatekeeper mutants can retain sensitivity to structurally similar but irreversible inhibitors suggest that steric hindrance may not explain the gatekeeper mechanism of resistance in all cases, and instead that the function of a gatekeeper mutation could be to bind ATP more strong…”
Background
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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