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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BackgroundInfluential
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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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