Cited by 2,118Lung Cancer Treatments and MutationsHER2/EGFR in Cancer ResearchProtein Kinase Regulation and GTPase Signaling

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The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP

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Yun, Cai-Hong, Mengwasser, Kristen E., Toms, Angela V., Woo, Michele S., Greulich, Heidi, Wong, Kwok-Kin, Meyerson, Matthew, Eck, Michael J.·2008·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0709662105PMC PMC2538882

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Abstract

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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10.1128/mcb.6.12.4155-4160.1986 · DOI

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A sulfonyl fluoride derivative inhibits EGFRL858R/T790M/C797S by covalent modification of the catalytic lysine
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“AKT, protein kinase B; C‐MET, tyrosine‐protein kinase Met; EGFR, epidermal growth factor receptor; EMT, epithelial‐mesenchymal transition; ERK, extracellular signal‐regulated kinase; FGFR1, fibroblast growth factor receptor 1; GAB1, GRB2‐associated binding protein 1; GRB2, growth factor receptor‐bound protein 2; HER2,…”
Background
The advance of the third‑generation EGFR‑TKI in the treatment of non‑small cell lung cancer (Review)
Cheng, Z., Cui, H., Wang, Y., Jin, Y., Lin, C., Shi, X., Zou, Y., Chen, J., Jia, X., & Su, L. (2023) · Oncology Reports · doi:10.3892/or.2023.8675 · Cited by 53
“On the other hand, the T790M muta‑ tion increased the binding ability of the L858R mutant to ATP, ultimately leading to drug resistance (34).”
Background
First-line treatment of EGFR-mutant non-small-cell lung cancer: the role of erlotinib and other tyrosine kinase inhibitors
Neal, J. W., & Nguyen, K.-S. H. (2012) · Biologics · doi:10.2147/btt.s26558 · Cited by 53
“46,47 In vitro studies show that T790M confers resistance to gefitinib, 46,48 possibly by increasing EGFR’s affinity for ATP, thus decreasing the binding of the ATP-competitive TKI.”
Structural biology contributions to tyrosine kinase drug discovery
Cowan‐Jacob, S. W., Möbitz, H., & Fabbro, D. (2009) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2009.01.012 · Cited by 54
Development of RET Kinase Inhibitors for Targeted Cancer Therapy
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Up-regulation of the Hippo pathway effector TAZ renders lung adenocarcinoma cells harboring EGFR-T790M mutation resistant to gefitinib
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“Accumulating evidence suggests that T790M-induced resistance is not only caused by lowering the affinity for gefitinib to nullify the hypersensitivity of activating EGFR mutations [14], but also attributed to the gain of”
Background
Utilizing protein structure to identify non-random somatic mutations
Ryslik, G. A., Cheng, Y., Cheung, K.-H., Modis, Y., & Zhao, H. (2013) · BMC Bioinformatics · doi:10.1186/1471-2105-14-190 · Cited by 51
Targeted Therapy for Medullary Thyroid Cancer: A Review
Priya, S. R., Dravid, C. S., Digumarti, R., & Dandekar, M. (2017) · Frontiers in Oncology · doi:10.3389/fonc.2017.00238 · Cited by 52
“org October 2017 | Volume 7 | Article 238 change blocking access to the drug (147); by alteration in the topography of target site (148); or by alteration in ATP affinity (149) and last but not least by gene amplification (150), by which the number of copies of the target gene is increased many times over to enable th…”
Background
A novel scaffold for EGFR inhibition: Introducing N-(3-(3-phenylureido)quinoxalin-6-yl) acrylamide derivatives
do Amaral, D. N., Lategahn, J., Fokoue, H. H., da Silva, E. M. B., Sant’Anna, C. M. R., Rauh, D., Barreiro, E. J., Laufer, S., & Lima, L. M. (2019) · Scientific Reports · doi:10.1038/s41598-018-36846-7 · Cited by 52
Secreted Phosphoprotein 1 (SPP1) Contributes to Second-Generation EGFR Tyrosine Kinase Inhibitor Resistance in Non-Small Cell Lung Cancer
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LS‐106, a novel EGFR inhibitor targeting C797S, exhibits antitumor activities both in vitro and in vivo
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Biochemical and structural basis for differential inhibitor sensitivity of EGFR with distinct exon 19 mutations
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“Yun et al 21 showed that for the L858R/T790M double mutant, affinity to gefitinib decreased four times, while affinity to ATP increased 18 times.”
High ratio of T790M to EGFR activating mutations correlate with the osimertinib response in non-small-cell lung cancer
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Lessons To Be Learned: The Molecular Basis of Kinase‐Targeted Therapies and Drug Resistance in Non‐Small Cell Lung Cancer
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The alteration of T790M between 19 del and L858R in NSCLC in the course of EGFR-TKIs therapy: a literature-based pooled analysis
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“The T790M mutation can be detected in nearly 50% patients at time of acquiring TKI- resistance (39).”
Background
Inhibition of osimertinib-resistant epidermal growth factor receptor EGFR-T790M/C797S
Lategahn, J., Keul, M., Klövekorn, P., Tumbrink, H. L., Niggenaber, J., Müller, M. P., Hodson, L. E., Flaßhoff, M., Hardick, J., Grabe, T., et al. (2019) · Chemical Science · doi:10.1039/c9sc03445e · Cited by 56
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“In cancer, RTKs can be selectively targeted using either small molecule ATP analogs (e.g., erlotinib for EGFR-positive non-small cell lung cancer (NSCLC)) or inhibitory monoclonal antibodies (e.g., trastuzumab for HER2-positive breast cancer).”
Background
Novel Irreversible Epidermal Growth Factor Receptor Inhibitors by Chemical Modulation of the Cysteine-Trap Portion
Carmi, C., Cavazzoni, A., Vezzosi, S., Bordi, F., Vacondio, F., Silva, C., Rivara, S., Lodola, A., Alfieri, R. R., Monica, S. L., et al. (2010) · Journal of Medicinal Chemistry · doi:10.1021/jm901558p · Cited by 51
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“The fact that T790M mutation increases recruitment and binding of ATP but not EGFR-TKIs and is found in 68% of NSCLC patients with defective responses to EGFR-TKIs [8] have strived for the exploration of irreversible-EGFR-TKIs such as afatinib.”
BackgroundInfluential
Integrated Multifunctional Electrochemistry Microchip for Highly Efficient Capture, Release, Lysis, and Analysis of Circulating Tumor Cells
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Molecular dynamics guided development of indole based dual inhibitors of EGFR (T790M) and c-MET
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Role of Osimertinib in the Treatment of EGFR-Mutation Positive Non-Small-Cell Lung Cancer
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Design, Synthesis, and Biological Evaluation of 6-Substituted Thieno[3,2-d]pyrimidine Analogues as Dual Epidermal Growth Factor Receptor Kinase and Microtubule Inhibitors
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Pyrazolo[3,4-d]pyrimidine-based dual EGFR T790M/HER2 inhibitors: Design, synthesis, structure–activity relationship and biological activity as potential antitumor and anticonvulsant agents
Lamie, P. F., El-Kalaawy, A. M., Latif, N. S. A., Rashed, L. A., & Philoppes, J. N. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113222 · Cited by 50
Bioinformatics Study of Sea Cucumber Peptides as Antibreast Cancer Through Inhibiting the Activity of Overexpressed Protein (EGFR, PI3K, AKT1, and CDK4)
Wargasetia, T. L., Ratnawati, H., Widodo, N., & Widyananda, M. H. (2021) · Cancer Informatics · doi:10.1177/11769351211031864 · Cited by 57
A Review on Fused Pyrimidine Systems as EGFR Inhibitors and Their Structure–Activity Relationship
Yadav, T., Shaikh, G. M., Kumar, M. S., Chintamaneni, M., & Mayur, Y. C. (2022) · Frontiers in Chemistry · doi:10.3389/fchem.2022.861288 · Cited by 54
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“A number of mechanisms for this acquired resistance have been identified, including a secondary T790M mutation at exon 20 of the EGFR gene [77–79], amplification of the MET proto-oncogene (MET) [80–82] or HER2”
Background
HPV – Das andere Kopf-Hals-Karzinom
Wittekindt, C., Wagner, S., Sharma, S. J., Würdemann, N., Knuth, J., Reder, H., & Klußmann, J. P. (2018) · Laryngo-Rhino-Otologie · doi:10.1055/s-0043-121596 · Cited by 58
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Centrosomal kinase Nek2 cooperates with oncogenic pathways to promote metastasis
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Chemical and Pathway Proteomics
Kruse, U., Bantscheff, M., Drewes, G., & Hopf, C. (2008) · Molecular & Cellular Proteomics · doi:10.1074/mcp.r800006-mcp200 · Cited by 48
“This apparent paradox was resolved by a quantitative analysis of ATP and drug binding to the EGFR (110).”
Background
AST1306, A Novel Irreversible Inhibitor of the Epidermal Growth Factor Receptor 1 and 2, Exhibits Antitumor Activity Both In Vitro and In Vivo
Xie, H., Lin, L., Tong, L., Jiang, Y., Zheng, M., Chen, Z., Jiang, X., Zhang, X., Ren, X., Qu, W., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0021487 · Cited by 48
“After incubating, the enzyme/inhibitor mixture is diluted 100-fold (i.e., to normal reaction conditions), reaction buffer plus ATP and substrate are added, and receptor kinase activity is measured continuously.”
BackgroundInfluential
Inhibition of mitochondrial glutaminase activity reverses acquired erlotinib resistance in non-small cell lung cancer
Xie, C., Jin, J., Bao, X., Zhan, W.-H., Han, T.-Y., Gan, M., Zhang, C., & Wang, J. (2016) · Oncotarget · doi:10.18632/oncotarget.6311 · Cited by 47
“Although the occurrence of genetic alterations such as T790M second mutation, MET amplification, hepatocyte growth factor (HGF) overexpression have been implicated [13–16], the precise mechanisms responsible for the acquired resistance to EGFR-TKIs still not well understood.”
Background
Molecular Dynamics Analysis of Binding of Kinase Inhibitors to WT EGFR and the T790M Mutant
Park, J., McDonald, J. J., Petter, R. C., & Houk, K. N. (2016) · Journal of Chemical Theory and Computation · doi:10.1021/acs.jctc.5b01221 · Cited by 47
Epidermal growth factor receptor inhibitors in oncology
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Discovery of 2,4,6-trisubstitued pyrido[3,4-d]pyrimidine derivatives as new EGFR-TKIs
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DFG-1 Residue Controls Inhibitor Binding Mode and Affinity, Providing a Basis for Rational Design of Kinase Inhibitor Selectivity
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Computational Modeling of Structurally Conserved Cancer Mutations in the RET and MET Kinases: The Impact on Protein Structure, Dynamics, and Stability
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“However, T790M resistance is complex and can be modified by concurrent mutations such as L858R, while gefitinib binding was unaffected by the dual T790M/L858R tumour yet resistance in this case emerged due to increased ATP affinity in the setting of the L858R variant [193,194].”
Background
Treatment Strategies for Non-Small Cell Lung Cancer with Common EGFR Mutations: A Review of the History of EGFR TKIs Approval and Emerging Data
Marin-Acevedo, J. A., Pellini, B., Kimbrough, E. O., Hicks, J. K., & Chiappori, A. (2023) · Cancers · doi:10.3390/cancers15030629 · Cited by 52
Blockade of DNA methylation enhances the therapeutic effect of gefitinib in non-small cell lung cancer cells
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“Three NSCLC cell lines with different EGFR mutation statuses and levels of sensitivity to EGFR-TKIs, obtained from the Shanghai Cell Station, Chinese Academy of Sciences, Shanghai, China were used: H1650 (del E746-A750), H1299 (wild-type EGFR) and PC-9 (del E746A750).”
BackgroundInfluential

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.
ORCID: Yun, Cai-Hong
Greulich, Heidi
Wong, Kwok-Kin
Meyerson, Matthew
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
DOI: 10.1073/pnas.0709662105
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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The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP

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