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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[20] Processing of X-ray diffraction data collected in oscillation mode
Otwinowski, Z., & Minor, W. (1997) · Methods in Enzymology · doi:10.1016/s0076-6879(97)76066-x · Cited by 33,475
Coot : model-building tools for molecular graphics
Emsley, P., & Cowtan, K. (2004) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444904019158 · Cited by 30,571
Crystallography & NMR System: A New Software Suite for Macromolecular Structure Determination
Brünger, A. T., Adams, P. D., Clore, G. M., DeLano, W. L., Gros, P., Grosse‐Kunstleve, R. W., Jiang, J., Kuszewski, J. J., Nilges, M., Pannu, N., et al. (1998) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444998003254 · Cited by 15,723
Refinement of Macromolecular Structures by the Maximum-Likelihood Method
Murshudov, G. N., Vagin, A. A., & Dodson, E. J. (1997) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444996012255 · Cited by 14,796
Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non–Small-Cell Lung Cancer to Gefitinib
Lynch, T. J., Bell, D. W., Sordella, R., Gurubhagavatula, S., Okimoto, R. A., Brannigan, B. W., Harris, P. L., Haserlat, S. M., Supko, J. G., Haluska, F. G., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa040938 · Cited by 11,486
EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy
Paez, J. G., Jänne, P. A., Lee, J. C., Tracy, S., Greulich, H., Gabriel, S., Herman, P., Kaye, F. J., Lindeman, N., Boggon, T. J., et al. (2004) · Science · doi:10.1126/science.1099314 · Cited by 9,368
Self-citation
PRODRG: a tool for high-throughput crystallography of protein–ligand complexes
Schüttelkopf, A. W., & van Aalten, D. M. F. (2004) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444904011679 · Cited by 4,837
EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib
Pao, W., Miller, V., Zakowski, M., Doherty, J., Politi, K., Sarkaria, I., Singh, B., Heelan, R., Rusch, V., Fulton, L., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0405220101 · Cited by 4,338
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Kobayashi, S., Boggon, T. J., Dayaram, T., Jänne, P. A., Kocher, O., Meyerson, M., Johnson, B. E., Eck, M. J., Tenen, D. G., & Halmos, B. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa044238 · Cited by 3,964
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Pao, W., Miller, V. A., Politi, K. A., Riely, G. J., Somwar, R., Zakowski, M. F., Kris, M. G., & Varmus, H. (2005) · PLoS Medicine · doi:10.1371/journal.pmed.0020073 · Cited by 3,527

Show all 42 references

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10.1128/mcb.6.12.4155-4160.1986 · DOI

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Nicotinamide Phosphoribosyltransferase: A Potent Therapeutic Target in Non-small Cell Lung Cancer with Epidermal Growth Factor Receptor-Gene Mutation
Okumura, S., Sasaki, T., Minami, Y., & Ohsaki, Y. (2011) · Journal of Thoracic Oncology · doi:10.1097/jto.0b013e318233d686 · Cited by 43
Intra-tumor heterogeneity: lessons from microbial evolution and clinical implications
de Bruin, E. C., Taylor, T., & Swanton, C. (2013) · Genome Medicine · doi:10.1186/gm505 · Cited by 44
“Nevertheless, as the T790M mutation has been detected in tumors in the absence of the drug, albeit at low frequency, and has been shown to enhance EGFR activity in experiments in vitro [81-83], it is currently unclear whether the reduced growth rate is due to the T790M mutation itself or to other mutations that might…”
Zielgerichtete kovalente Inhibitoren für das Wirkstoffdesign
Baillie, T. A. (2016) · Angewandte Chemie · doi:10.1002/ange.201601091 · Cited by 42
Structural insights into drug development strategy targeting EGFR T790M/C797S
Zhu, S., Zhao, P., Yang, J., Ma, R., Yan, X.-E., Yang, S., Yang, J., & Yun, C. (2018) · Oncotarget · doi:10.18632/oncotarget.24113 · Cited by 42
“We previously showed that T790M mutation dramatically increases the ATP binding affinity of the oncogenic activating mutants and weakens the binding affinity of the drugs, hence reducing the potency of any ATP-competitive inhibitors [13].”
InfluentialSelf-citation
Heterogeneity and mutation in KRAS and associated oncogenes: evaluating the potential for the evolution of resistance to targeting of KRAS G12C
Cannataro, V. L., Gaffney, S. G., Stender, C., Zhao, Z.-M., Philips, M. R., Greenstein, A. E., & Townsend, J. P. (2018) · Oncogene · doi:10.1038/s41388-017-0105-z · Cited by 43
Bisphosphonate-Generated ATP-Analogs Inhibit Cell Signaling Pathways
Malwal, S. R., O’Dowd, B., Feng, X., Turhanen, P. A., Shin, C. J., Yao, J., Kim, B. K., Baig, N., Zhou, T. H., Bansal, S., et al. (2018) · Journal of the American Chemical Society · doi:10.1021/jacs.8b02363 · Cited by 42
Introducing of acyclonucleoside analogues tethered 1,2,4-triazole as anticancer agents with dual epidermal growth factor receptor kinase and microtubule inhibitors
Aouad, M. R., Al-Mohammadi, H. M., Al-blewi, F. F., et al. (2019) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2019.103446 · Cited by 42
Emerging roles of the αC‐β4 loop in protein kinase structure, function, evolution, and disease
Yeung, W., Ruan, Z., & Kannan, N. (2020) · IUBMB Life · doi:10.1002/iub.2253 · Cited by 39
“In the αC-β4 loop, the HxN + 1 and HxN + 2 positions are spatially proximal to the gatekeeper position: a wellstudied hotspot for secondary drug resistance mutations.(75,76) Mutations at HxN + 1 and HxN + 2 positions have been associated with drug resistance in several tyrosine kinases.”
Background
Design, synthesis, anticancer activity and docking studies of novel quinazoline-based thiazole derivatives as EGFR kinase inhibitors
Raghu, M. S., Swarup, H. A., Shamala, T., Prathibha, B. S., Kumar, K. Y., Alharethy, F., Prashanth, M. K., & Jeon, B. (2023) · Heliyon · doi:10.1016/j.heliyon.2023.e20300 · Cited by 44
“These medications raise concerns due to their developed drug resistance and significant adverse effects [5,6].”
Enhancing cellular immunotherapies in cancer by engineering selective therapeutic resistance
Wellhausen, N., Baek, J. S., Gill, S. I., & June, C. H. (2024) · Nature reviews. Cancer · doi:10.1038/s41568-024-00723-5 · Cited by 45
“Another example is the T790M mutation in epidermal growth factor receptor (EGFR), which was identified in non-small-cell lung cancer and can confer resistance to TKIs by increasing the ATP affinity of EGFR 33 .”
Hsp90 Inhibition Overcomes HGF-Triggering Resistance to EGFR-TKIs in EGFR-Mutant Lung Cancer by Decreasing Client Protein Expression and Angiogenesis
Koizumi, H., Yamada, T., Takeuchi, S., et al. (2012) · Journal of Thoracic Oncology · doi:10.1097/jto.0b013e3182519a2c · Cited by 41
Src inhibitors act through different mechanisms in Non-Small Cell Lung Cancer models depending on EGFR and RAS mutational status
Formisano, L., D'Amato, V., Servetto, A., Brillante, S., Raimondo, L., Mauro, C. D., Marciano, R., Orsini, R. C., Cosconati, S., Randazzo, A., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.4636 · Cited by 42
Clinical outcomes of advanced non-small-cell lung cancer patients with EGFR mutation, ALK rearrangement and EGFR/ALK co-alterations
Lou, N.-N., Zhang, X., Chen, H., Zhou, Q. H., Yan, L., Xie, Z., Su, J., Chen, Z., Tu, H., Yan, H., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.11218 · Cited by 43
“The T790M mutation is thought to reactivate EGFR signaling by increasing the receptor’s affinity for ATP over TKIs [32] This mutation is also thought to amplify the expression of components of the hepatocyte growth factor receptor and mesenchymal epithelial transition (MET) pathways [27, 33–36] In addition, PIK3CA and…”
Background
The association between anti-tumor potency and structure-activity of protein-kinases inhibitors based on quinazoline molecular skeleton
Li, Y., Xiao, J., Zhang, Q., Yu, W., Liu, M., Guo, Y. C., He, J., & Liu, Y. (2018) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2018.12.032 · Cited by 43
Harnessing Reversed Allosteric Communication: A Novel Strategy for Allosteric Drug Discovery
Fan, J., Liu, Y., Kong, R., Ni, D., Yu, Z., Lu, S., & Zhang, J. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c01695 · Cited by 43
Kinase-targeting small-molecule inhibitors and emerging bifunctional molecules
Goebel, G. L., Qiu, X., & Wu, P. (2022) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2022.04.006 · Cited by 44
Discovery of mobocertinib, a new irreversible tyrosine kinase inhibitor indicated for the treatment of non-small-cell lung cancer harboring EGFR exon 20 insertion mutations
Wang, J., Lam, D., Yang, J., & Hu, L. (2022) · Medicinal Chemistry Research · doi:10.1007/s00044-022-02952-5 · Cited by 43
“the pyrimidine ring, ii) mobocertinib is active and selective for all variants of EGFR exon 20 mutants, including T790M [43], iii) the T790M mutation was found not to directly impede drug binding in the active site; binding mode of an irreversible TKI to T790M was found to be essentially the same as that in the wild t…”
Background
The Role of Irreversible EGFR Inhibitors in the Treatment of Non-Small Cell Lung Cancer: Overcoming Resistance to Reversible EGFR Inhibitors
Belani, C. P. (2010) · Cancer Investigation · doi:10.3109/07357901003631072 · Cited by 41
“Alternatively, T790M has been shown to increase the binding affinity of ATP by more than 10-fold, at least when EGFR carries the L858R primary activating mutation (49).”
Targeted nanoconjugate co-delivering siRNA and tyrosine kinase inhibitor to KRAS mutant NSCLC dissociates GAB1-SHP2 post oncogene knockdown
Srikar, R., Suresh, D., Zambre, A., Taylor, K., Chapman, S., Leevy, M., Upendran, A., & Kannan, R. (2016) · Scientific Reports · doi:10.1038/srep30245 · Cited by 43
EGFR-targeted therapy results in dramatic early lung tumor regression accompanied by imaging response and immune infiltration in EGFR mutant transgenic mouse models
Venugopalan, A., Lee, M.-J., Niu, G., Medina-Echeverz, J., Tomita, Y., Lizak, M. J., Cultraro, C. M., Simpson, R. M., Chen, X., Trepel, J. B., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.11021 · Cited by 40
“As expected, however, erlotinib has proven ineffective against EGFR-TKIresistant EGFRL858R/T790M-driven tumors [11, 35].”
Background
A fluorogenic probe for predicting treatment response in non-small cell lung cancer with EGFR-activating mutations
Deng, H., Lei, Q., Wang, C., Wang, Z., Chen, H., Wang, G., Yang, N. Y., Huang, D. A., Yu, Q., Yao, M., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-34627-5 · Cited by 40
Design, synthesis and biological evaluation of novel 6-alkenylamides substituted of 4-anilinothieno[2,3-d]pyrimidines as irreversible epidermal growth factor receptor inhibitors
Ji, X., Peng, T., Zhang, X., Li, J., Yang, W., Tong, L., Qu, R., Jiang, H., Ding, J., Xie, H., et al. (2014) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2014.01.035 · Cited by 40
A systematic profile of clinical inhibitors responsive to EGFR somatic amino acid mutations in lung cancer: implication for the molecular mechanism of drug resistance and sensitivity
Ai, X., Sun, Y., Wang, H., & Lü, S. (2014) · Amino Acids · doi:10.1007/s00726-014-1716-0 · Cited by 40
“Previous experimental evidences suggested that the increased ATP affinity is a primary mechanism by which the T790M mutation confers drug resistance (Yun et al. 2008)—this can be well reflected in the calculated mutation energy profile (Fig.”
Influential
Changes in Plasma Mass-Spectral Profile in Course of Treatment of Non-small Cell Lung Cancer Patients with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors
Lazzari, C., Spreafico, A., Bachi, A., Röder, H., Floriani, I., Garavaglia, D., Cattaneo, A., Grigorieva, J., Viganò, M. G., Sorlini, C., et al. (2011) · Journal of Thoracic Oncology · doi:10.1097/jto.0b013e3182307f17 · Cited by 40
The Potential of panHER Inhibition in Cancer
Wang, X., Batty, K., Crowe, P. J., Goldstein, D., & Yang, J. (2015) · Frontiers in Oncology · doi:10.3389/fonc.2015.00002 · Cited by 40
“The T790M mutation is believed to account for 50% of the resistance to the aforementioned drugs (43).”
Background
Understanding Mechanisms of Resistance in the Epithelial Growth Factor Receptor in Non-Small Cell Lung Cancer and the Role of Biopsy at Progression
Socinski, M. A., Villaruz, L. C., & Ross, J. S. (2016) · The Oncologist · doi:10.1634/theoncologist.2016-0285 · Cited by 40
Exploring Covalent Allosteric Inhibition of Antigen 85C from Mycobacterium tuberculosis by Ebselen Derivatives
Goins, C. M., Dajnowicz, S., Thanna, S., Sucheck, S. J., Parks, J. M., & Ronning, D. R. (2017) · ACS Infectious Diseases · doi:10.1021/acsinfecdis.7b00003 · Cited by 41
Deciphering mechanisms of acquired T790M mutation after EGFR inhibitors for NSCLC by computational simulations
Zou, B., Lee, V. H.-F., Chen, L., Ma, L., Wang, D. D., & Yan, H. (2017) · Scientific Reports · doi:10.1038/s41598-017-06632-y · Cited by 40
“Another explanation is that introduction of the T790M mutation increases the affinity for adenosine triphosphate (ATP) which in turn causes reduced binding of the ATP-competitive TKI including gefitinib and erlotinib 20, 21, 23 .”
Background
Epithelial‐to‐mesenchymal transition in the context of epidermal growth factor receptor inhibition in non‐small‐cell lung cancer
Bronte, G., Bravaccini, S., Bronte, E., Burgio, M. A., Rolfo, C. D., Delmonte, A., & Crinò, L. (2018) · Biological reviews/Biological reviews of the Cambridge Philosophical Society · doi:10.1111/brv.12416 · Cited by 38
“Consequently, binding to ATP is restored to the same level as wild-type EGFR (Yun et al., 2008).”
Background
Loss of T790M mutation is associated with early progression to osimertinib in Chinese patients with advanced NSCLC who are harboring EGFR T790M
Zhao, S., Li, X., Zhao, C., Jiang, T., Jia, Y., Shi, J., He, Y., Li, J., Zhou, F., Gao, G., et al. (2018) · Lung Cancer · doi:10.1016/j.lungcan.2018.12.010 · Cited by 40
Mediating EGFR-TKI Resistance by VEGF/VEGFR Autocrine Pathway in Non-Small Cell Lung Cancer
Osude, C., Lin, L. Y.-C., Patel, M., Eckburg, A., Berei, J., Kuckovic, A., Dube, N., Rastogi, A., Gautam, S., Smith, T. J., et al. (2022) · Cells · doi:10.3390/cells11101694 · Cited by 41
“The T790M mutation causes resistance to TKIs by way of steric hindrance, which interrupts TKI binding to the ATP binding pocket [44].”
Background
Mechanisms of resistance to EGFR inhibitors in head and neck cancer
Cooper, J. B., & Cohen, E. E. W. (2009) · Head & Neck · doi:10.1002/hed.21109 · Cited by 39
“These double mutants also have higher activity relative to simple L858R mutants due to the T790M mutation.(40) T790M also seems to mediate resistance to HKI-272, an irreversible TKI similar to the aforementioned, at low physiological concentrations in NSCLC.”
Background
Role of repair protein Rad51 in regulating the response to gefitinib in human non-small cell lung cancer cells
Ko, J., Hong, J.-H., Wang, L.-H., Cheng, C.-M., Ciou, S., Lin, S., Jheng, M.-Y., & Lin, Y. (2008) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-08-0578 · Cited by 40
“A recent report has revealed that MET amplification occurs independently of EGFR (T790M) mutations and that MET may be a clinically relevant therapeutic target for some patients with acquired resistance to small-molecule TKIs (46).”
Background
Non-small cell lung cancer - genetic predictors
Koudeláková, V., Kneblova, M., Trojanec, R., Drábek, J., & Hajdúch, M. (2013) · Biomedical Papers · doi:10.5507/bp.2013.034 · Cited by 39
BCR::ABL1 kinase N-lobe mutants confer moderate to high degrees of resistance to asciminib
Leyte-Vidal, A., Garrido Ruiz, D., DeFilippis, R., Leske, I. B., Rea, D., Phan, S., Miller, K. B., Hu, F., Mase, A., Shan, Y., et al. (2024) · Blood · doi:10.1182/blood.2023022538 · Cited by 40
Tumor heterogeneity: evolution through space and time in EGFR mutant non small cell lung cancer patients.
Majem, M., & Remón, J. (2013) · Europe PMC (PubMed Central) · doi:10.3978/j.issn.2218-6751.2013.03.09 · Cited by 41
“This gatekeeper mutation also occurs within exon 20, which encodes part of the kinase domain EGFR and alters the binding of EGFR TKI to the ATPbinding pocket, and therefore EGFR TKI are unable to block EGFR signalling (20-22).”
Background
Targeted Inhibition of Kinases in Cancer Therapy
Baker, S. J., & Reddy, E. P. (2010) · Mount Sinai Journal of Medicine A Journal of Translational and Personalized Medicine · doi:10.1002/msj.20220 · Cited by 39
Structure-Based Network Analysis of Activation Mechanisms in the ErbB Family of Receptor Tyrosine Kinases: The Regulatory Spine Residues Are Global Mediators of Structural Stability and Allosteric Interactions
James, K. A., & Verkhivker, G. M. (2014) · PLoS ONE · doi:10.1371/journal.pone.0113488 · Cited by 40
Targeted Covalent Enzyme Inhibitors
Noe, M. C., & Gilbert, A. M. (2012) · Annual reports in medicinal chemistry · doi:10.1016/b978-0-12-396492-2.00027-8 · Cited by 39
Analysis of progression-free survival of first-line tyrosine kinase inhibitors in patients with non-small cell lung cancer harboring leu858Arg or exon 19 deletions
Kuan, F., Li, S., Wang, C., Lin, M., Tsai, Y., & Yang, C. (2016) · Oncotarget · doi:10.18632/oncotarget.13815 · Cited by 40
The latest therapeutic strategies after resistance to first generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in patients with non-small cell lung cancer (NSCLC).
Xu, M. M., Xie, Y., Ni, S., & Liu, H. (2015) · Europe PMC (PubMed Central) · doi:10.3978/j.issn.2305-5839.2015.03.60 · Cited by 41
“T790M mutation which prevents drug binding to the domain through steric hindrance, but the combination of ATP and tyrosine kinase was not affected, facilitates continued signal transduction (12,13).”
Background
Raman micro-spectroscopy monitors acquired resistance to targeted cancer therapy at the cellular level
Hammoud, M. K., Yosef, H. K., Lechtonen, T., Aljakouch, K., Schuler, M., Alsaidi, W., Daho, I., Maghnouj, A., Hahn, S. A., El‐Mashtoly, S. F., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-33682-7 · Cited by 42
The EGFR T790M Mutation Is Acquired through AICDA-Mediated Deamination of 5-Methylcytosine following TKI Treatment in Lung Cancer
Kadi, N. E., Wang, L., Davis, A., Körkaya, H., Cooke, A., Vadnala, V., Brown, N. A., Betz, B. L., Cascalho, M., Kalemkerian, G. P., et al. (2018) · Cancer Research · doi:10.1158/0008-5472.can-17-3370 · Cited by 41
“This T790M mutation occurs in cis with the original driving mutation, and leads to steric hindrance and increased binding affinity for ATP (16, 17).”
Development of a Novel EGFR-Targeting Antibody-Drug Conjugate for Pancreatic Cancer Therapy
Li, Z., Wang, M., Yao, X., et al. (2019) · Targeted Oncology · doi:10.1007/s11523-018-0616-8 · Cited by 39
Lung Adenocarcinoma: Lessons in Translation from Bench to Bedside
Sangodkar, J., Katz, S., Melville, H., & Narla, G. (2010) · Mount Sinai Journal of Medicine A Journal of Translational and Personalized Medicine · doi:10.1002/msj.20226 · Cited by 38

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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