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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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“One example of this is the identification of the T790M mutation in the EGFR gene in lung adenocarcinomas (Yun et al, 2008).”
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A covalently bound inhibitor triggers EZH2 degradation through CHIP‐mediated ubiquitination
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Santarpía, M., Liguori, A., Karachaliou, N., González‐Cao, M., Daffinà, M. G., D’Aveni, A., Marabello, G., Altavilla, G., & Rosell, R. (2017) · Lung Cancer Targets and Therapy · doi:10.2147/lctt.s119644 · Cited by 104
“The presence of T790M can also restore the affinity of mutant receptor for ATP, thus reducing the potency of competitive inhibitors.(53) The identification of T790M prompted the development of different therapeutic strategies to overcome resistance.”
EGFR mutations in lung cancer: from tissue testing to liquid biopsy
Fenizia, F., Luca, A. D., Pasquale, R., Sacco, A., Forgione, L., Lambiase, M., Iannaccone, A., Chicchinelli, N., Franco, R., Rossi, A., et al. (2015) · Future Oncology · doi:10.2217/fon.15.23 · Cited by 95
Circulating Cell Free Tumor DNA Detection as a Routine Tool forLung Cancer Patient Management
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“The T790M mutation is present in about half of the lung cancer patients with acquired resistance, and is reported to increase the affinity of the receptor to ATP, relative to its affinity to TKIs [2].”
BackgroundAcquired Resistance to Drugs Targeting Tyrosine Kinases
Rosenzweig, S. A. (2018) · Advances in cancer research · doi:10.1016/bs.acr.2018.02.003 · Cited by 93
QM/MM Calculations in Drug Discovery: A Useful Method for Studying Binding Phenomena?
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β-Catenin Contributes to Lung Tumor Development Induced by EGFR Mutations
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“As EGFRL858R and L858R-T790M show high levels of constitutive tyrosine kinase activity (3, 33), we first asked whether EGFR mutants tyrosine-phosphorylate β-catenin.”
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“The substitution of threonine for methionine at amino acid position 790 (T790M) in exon20 of EGFR translates to reduced binding of first-generation EGFR TKIs due to steric hindrance, which concomitantly restores ATP binding affinity similar to that of WT EGFR (32).”
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“[154] showed that the Met766 residue can shift to accommodate inhibitor binding, and proposed instead that resistance can be accounted for by the greatly increased ATP-binding affinity (~8-fold) for T766M-EGFR, results later validated by Yoshikawa et al.”
ResultDiscovery and Optimization of Dibenzodiazepinones as Allosteric Mutant-Selective EGFR Inhibitors
Clercq, D. J. H. D., Heppner, D. E., To, C., Jang, J., Park, E., Yun, C., Mushajiang, M., Shin, B. H., Gero, T. W., Scott, D. A., et al. (2019) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.9b00381 · Cited by 100
Self-citationCan EGFR be a therapeutic target in breast cancer?
Li, X., Zhao, L., Chen, C., Nie, J., & Jiao, B. (2022) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2022.188789 · Cited by 96
Chhouri, H., Alexandre, D., & Grumolato, L. (2023) · Cancers · doi:10.3390/cancers15020504 · Cited by 103
“It has been shown that this mutation prevents drug binding by increasing the affinity of the mutant receptor for ATP, thus reducing the potency of ATP competitive EGFR-TKIs [29].”
BackgroundProfile of neratinib and its potential in the treatment of breast cancer
Kong, A. H., & Feldinger, K. (2015) · Breast Cancer Targets and Therapy · doi:10.2147/bctt.s54414 · Cited by 99
“67 However, secondary resistance is common due to an alternative T790M mutation, which causes increased affinity for ATP.”
InfluentialReguart, N., & Remon, J. (2015) · Future Oncology · doi:10.2217/fon.15.15 · Cited by 91
Therapeutic value of EGFR inhibition in CRC and NSCLC: 15 years of clinical evidence
Troiani, T., Napolitano, S., Della Corte, C. M., Martini, G., Martinelli, E., Morgillo, F., & Ciardiello, F. (2016) · ESMO Open · doi:10.1136/esmoopen-2016-000088 · Cited by 104
“Other novel EGFR ectodomain mutations have been found and are under scrutiny.72 Similarly, in NSCLC, a secondary mutation in EGFR exon 20 (T790M) occurred in more than 50% of cases of TKIs resistance.82 T790M is a substitution of methionine for threonine in position 790 in kinase domain; this substitution altered the…”
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Leroy, E., & Constantinescu, S. N. (2017) · Leukemia · doi:10.1038/leu.2017.43 · Cited by 92
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Self-citationNoncovalent Wild-type–Sparing Inhibitors of EGFR T790M
Lee, H.-J., Schaefer, G., Heffron, T. P., Shao, L., Ye, X., Sideris, S., Malek, S., Chan, E., Merchant, M., La, H., et al. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0357 · Cited by 90
EGFR: The Paradigm of an Oncogene-Driven Lung Cancer
Riely, G. J., & Yu, H. A. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-3154 · Cited by 91
“mutation inEGFR is thought to alter kinaseATPaffinity above that of gefitinib or erlotinib (35).”
BackgroundDrug Resistance to EGFR Inhibitors in Lung Cancer
Tetsu, O., Hangauer, M. J., Phuchareon, J., Eisele, D. W., & McCormick, F. P. (2016) · Chemotherapy · doi:10.1159/000443368 · Cited by 88
EGFR Family Members’ Regulation of Autophagy Is at a Crossroads of Cell Survival and Death in Cancer
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“However, mutations such as T790M change make cancer cells become resistant to these drugs [27].”
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“Concomitant with the exciting advancements in this field is the emergence of drug resistance (1-3), with the substitution of methionine for threonine at position 790 (T790M) being the most commonly acquired resistance mutation, accounting for approximately 50% of resistant cases.”
BackgroundThe molecular basis of targeting protein kinases in cancer therapeutics
Tsai, C., & Nussinov, R. (2013) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2013.04.001 · Cited by 91
Cell signaling and cancer: a mechanistic insight into drug resistance
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Targeting epidermal growth factor receptor: Central signaling kinase in lung cancer
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“Recent study has also shown that the affinity of ATP-binding to the cleft is increased by the presence of T790M [99], explaining”
BackgroundNeratinib: an oral, irreversible dual EGFR/HER2 inhibitor for breast and non-small cell lung cancer
Bose, P., & Ozer, H. (2009) · Expert Opinion on Investigational Drugs · doi:10.1517/13543780903305428 · Cited by 89
“An irreversible inhibitor is noncompetitive with ATP, and would be unaffected by high concentrations of ATP within the cell.”
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Lahti, J. L., Tang, G. W., Capriotti, E., Liu, T., & Altman, R. B. (2012) · Journal of The Royal Society Interface · doi:10.1098/rsif.2011.0843 · Cited by 89
Aljakouch, K., Lechtonen, T., Yosef, H. K., Hammoud, M. K., Alsaidi, W., Kötting, C., Mügge, C., Kourist, R., El‐Mashtoly, S. F., & Gerwert, K. B. (2018) · Angewandte Chemie International Edition · doi:10.1002/anie.201803394 · Cited by 89
Epidermal Growth Factor Receptor: Pathway, Therapies, and Pipeline
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“Although this process makes them potentially more effective, including in the setting of the T790M mutation, direct comparisons are pending.(75) Second-generation agents have completed Phase III study.”
BackgroundActivating Mutations in ERBB2 and Their Impact on Diagnostics and Treatment
Herter-Sprie, G. S., Greulich, H. E., & Wong, K. (2013) · Frontiers in Oncology · doi:10.3389/fonc.2013.00086 · Cited by 88
“The gatekeeper mutation enhances the affinity of the oncogenic form of the receptor for ATP, allowing continued proliferation in the presence of the drug (Yun et al., 2008).”
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“Drug resistance caused by EGFR mutations has been a major issue of antineoplastic therapy failure in using EGFR inhibitors [5].”
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“One of the most effective strategies to stop EGFR activity is to block its interactions with ATP, so EGFR cannot activate several pathways after activating (Yun et al., 2008).”
BackgroundXu, X., Mao, L., Xu, W., Tang, W., Zhang, X., Xi, B., Xu, R., Fang, X., Liu, J., Fang, C., et al. (2016) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-16-0281 · Cited by 87
“There are at least two mechanisms that contribute to the acquired resistance: (i) the emergence of the gatekeeper T790M EGFR mutation, which prevents binding of the gefitinib and erlotinib to EGFR, and (ii) the up-regulation of a bypass track which activate downstream signals (12-15).”
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“In the following sections, we present completed and ongoing efforts to overcome resistance and an algorithm of treatment strategies for patients with systemic progression after an initial response to EGFR TKIs.”
BackgroundInfluentialManagement of Brain Metastases in Epidermal Growth Factor Receptor Mutant Non-Small-Cell Lung Cancer
Kelly, W., Shah, N. J., & Subramaniam, D. S. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00208 · Cited by 86
“The T790M mutation also increases ATP affinity (16).”
BackgroundMartorana, A., Monica, G. L., & Lauria, A. (2020) · Molecules · doi:10.3390/molecules25184279 · Cited by 92
Zaidman, D., Gehrtz, P., Filep, M., Fearon, D., Gabizon, R., Douangamath, A., Prilusky, J., Duberstein, S., Cohen, G., Owen, C. D., et al. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.05.018 · Cited by 85
“, 2015), (2) an ability to compete with highaffinity natural substrates (Lonsdale andWard, 2018; Michalczyk et al., 2008; Yun et al., 2008),(3) their improved selectivity when targeting non-conserved cysteine residues (Cohen et al.”
BackgroundHaaland, B. A., Tan, P. S., de Castro, G., & Lopes, G. D. L., Jr. (2014) · Journal of Thoracic Oncology · doi:10.1097/jto.0000000000000156 · Cited by 84
“This mutation sterically prevents reversible binding of gefitinib or erlotinib,(30) but it can potentially be overcome by TKIs such as afatinib, which binds irreversibly to the receptor.(8,30) However, our meta-analysis did not show superiority of afatinib over gefitinib or erlotinib in terms of progressionfree surviv…”
BackgroundFoo, J., Chmielecki, J., Pao, W. J., & Michor, F. (2012) · Journal of Thoracic Oncology · doi:10.1097/jto.0b013e31826146ee · Cited by 85
“2012;7: 1583–1593) Erlotinib (Tarceva; OSI Pharmaceuticals, Farmingdale, NY) is an orally active selective inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase.1 More than 70% of patients with non–small-cell lung cancer (NSCLC) harboring specific mutations in the EGFR kinase domain exhibit a radiog…”
BackgroundShaurova, T., Zhang, L., Goodrich, D. W., & Hershberger, P. A. (2020) · Frontiers in Genetics · doi:10.3389/fgene.2020.00281 · Cited by 82
“For instance, the T790M, or “gatekeeper” mutation, increases receptor binding affinity for ATP, resulting in loss of response to early generation TKIs (Yun et al., 2008).”
BackgroundAdvances in Target Therapy for Lung Cancer
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“A typical example is EGFR-TKI as described.”
BackgroundInfluentialRe, M. D., Tiseo, M., Bordi, P., D’Incecco, A., Camerini, A., Petrini, I., Lucchesi, M., Inno, A., Spada, D., Vasile, E., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.6957 · Cited by 85
“In addition to this, the present study provides evidence that sensitizing MUTEGFR and MUTKRAS can coexist after the selective pressure of EGFR-TKI treatment. p.T790MEGFR determines acquired resistance by increasing the affinity of EGFR to ATP [16, 17]. p.T790MEGFR has been described in re-biopsies of 50–63% of tumors…”
BackgroundBrain metastases in oncogene-driven non-small cell lung cancer
Nishino, M., Soejima, K., & Mitsudomi, T. (2019) · Translational Lung Cancer Research · doi:10.21037/tlcr.2019.05.15 · Cited by 84
“However, life-time incidence of brain metastases in NSCLC patients with EGFR mutation is reported to be higher compared to those with wild-type EGFR (70% in EGFR, 38% in EGFR) (42).”
BackgroundMechanisms of EGFR Resistance in Glioblastoma
Pan, P., & Magge, R. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21228471 · Cited by 88
“the same paper that T790M markedly increases and restores the affinity of L858R for ATP [38].”
BackgroundMechanisms of resistance to tyrosine kinase inhibitor‐targeted therapy and overcoming strategies
Ou, X., Gao, G., Habaz, I. A., & Wang, Y. (2024) · MedComm · doi:10.1002/mco2.694 · Cited by 104
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“The T790M mutation increases the affinity of EGFR for ATP, decreasing the binding of EGFR to EGFR-TKIs and inducing resistance to the latter agents (36).”
BackgroundMechanisms for Kinase-mediated Dimerization of the Epidermal Growth Factor Receptor
Lu, C., Mi, L.-Z., Schürpf, T., Walz, T., & Springer, T. A. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.414391 · Cited by 83
“On the other hand, lapatinib and HKI-272 are inhibitors that stabilize the kinase in inactive conformation by pushing the kinase C-helix out of its active state (19, 30).”
BackgroundChang, S., Zhang, L., Xu, S., Luo, J., Lu, X., Zhang, Z., Xu, T., Liu, Y., Tu, Z., Xu, Y., et al. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm201591k · Cited by 85
Therapeutic strategy for advanced EGFR mutant non-small-cell lung carcinoma
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“The moleclar mechanism consists of a conformational change of the TP pocket, which increases receptor affinity for ATP while ecreasing its affinity for TKI [105].”
Lind, J. S. W., Dingemans, A. C., Groen, H. J. M., Thunnissen, E., Bekers, O., Heideman, D. A. M., Honeywell, R. J., Giovannetti, E., Peters, G. J., Postmus, P. E., et al. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-3033 · Cited by 82
Oncogenic JAK1 and JAK2-activating mutations resistant to ATP-competitive inhibitors
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“Further structural data are necessary to determine whether a critical interaction also takes place between Phe958 and INCB018424 or other inhibitors used in this study, but the observation that these JAK mutations confer resistance to different ATP-competitive inhibitors and that they are activating mutations is more…”
BackgroundChemoresistance in Cancer Cells: Exosomes As Potential Regulators of Therapeutic Tumor Heterogeneity
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Discovery of Potent PROTACs Targeting EGFR Mutants through the Optimization of Covalent EGFR Ligands
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Sequence and Structure Signatures of Cancer Mutation Hotspots in Protein Kinases
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“Structural determinations of the EGFR [38–41] and ABL cancer mutants [42,43] have suggested that molecular mechanisms of kinase activation by cancer mutations and activity signatures of cancer drugs may be associated with the dynamics of functional transitions between inactive and active kinase forms.”
BackgroundMolecular Predictors of EGFR-TKI Sensitivity in Advanced Non–small Cell Lung Cancer
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“The introduction of T790M mutation increases ATP affinity of receptors, which relatively attenuates the binding of EGFR-TKIs (48).”
BackgroundDixit, A., & Verkhivker, G. M. (2011) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1002179 · Cited by 83
“Another study revealed that EGFR-T790M could increase the ATP affinity back to the EGFR-WT level, which may lead to a reduced potency of any ATP-competitive agent [79,170].”
BackgroundMethodChemical strategies to overcome resistance against targeted anticancer therapeutics
Pisa, R., & Kapoor, T. M. (2020) · Nature Chemical Biology · doi:10.1038/s41589-020-0596-8 · Cited by 84
Cracking the EGFR code: Cancer biology, resistance mechanisms, and future therapeutic frontiers
Du, Y.-F., Karatekin, F., Wang, W. K., Hong, W., & Gandhi, T. K. B. (2025) · Pharmacological Reviews · doi:10.1016/j.pharmr.2025.100076 · Cited by 88
Resistance to EGF-R (erbB-1) and VEGF-R modulating agents
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Everolimus restores gefitinib sensitivity in resistant non-small cell lung cancer cell lines
Monica, S. L., Galetti, M., Alfieri, R. R., Cavazzoni, A., Ardizzoni, A., Tiseo, M., Capelletti, M., Goldoni, M., Tagliaferri, S., Mutti, A., et al. (2009) · Biochemical Pharmacology · doi:10.1016/j.bcp.2009.04.033 · Cited by 80
“The T790M mutation in the H1975 cell line conferred resistance to gefitinib enhancing the receptor catalytic activity [32], indeed in this cell line no difference was observed between untreated and gefitinib-treated cells.”
BackgroundPlaza-Menacho, I., Barnouin, K., Goodman, K. M., Martinez-Torres, R. J., Borg, A., Murray‐Rust, J., Mouilleron, S., Knowles, P. P., & McDonald, N. Q. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.01.015 · Cited by 79
“We verified that oncogenic RET M918T increases enzymatic activity and ATP affinity analogous to the T790M mutation of the EGFR (Yun et al., 2008).”
InfluentialLin, L., & Bivona, T. G. (2012) · Chemotherapy Research and Practice · doi:10.1155/2012/817297 · Cited by 85
“reduce the potency of an ATP-competitive kinase inhibitor [41].”
BackgroundLiquid biopsy and non-small cell lung cancer: are we looking at the tip of the iceberg?
Bonanno, L., Maso, A. D., Pavan, A., Zulato, E., Calvetti, L., Pasello, G., Guarneri, V., Conte, P., & Indraccolo, S. (2022) · British Journal of Cancer · doi:10.1038/s41416-022-01777-8 · Cited by 81
“The second clinical application of liquid biopsy in EGFR mutation-positive NSCLC is the evaluation of the most common acquired resistance mechanism to first and second-generation EGFR-TKIs (erlotinib, gefitinib and afatinib): T790M mutation [55, 56] (Fig.”
BackgroundEmerging concepts in the regulation of the EGF receptor and other receptor tyrosine kinases
Endres, N., Barros, T. F., Cantor, A. J., & Kuriyan, J. (2014) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2014.08.001 · Cited by 79
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Brain Metastases in Oncogene-Addicted Non-Small Cell Lung Cancer Patients: Incidence and Treatment
Remón, J., & Besse, B. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00088 · Cited by 80
“The substitution of threonine to methionine at amino acid position 790 (T790M) in exon 20 of the EGFR gene reduces firstgeneration EGFR TKI binding by enhancing the ATP binding affinity of the kinase domain of the EGFR-mutant receptor (39).”
BackgroundChen, H., & Cheng, X. (2014) · OncoTargets and Therapy · doi:10.2147/ott.s66502 · Cited by 81
“EGFR of lung cancer cells with both TKI-sensitive mutations and T790M mutation regain affinity to ATP at the hydrophobic pocket, hence abrogating competitive inhibition of the receptor by gefitinib and erlotinib.(120) Other secondary mutations in the EGFR kinase domain that are associated with acquired resistance incl…”
Network-Based Modeling and Intelligent Data Mining of Social Media for Improving Care
Akay, A. R., Dragomir, A., & Erlandsson, B.-E. (2014) · IEEE Journal of Biomedical and Health Informatics · doi:10.1109/jbhi.2014.2336251 · Cited by 78
“According to chart, and from our readings of both the user posts and the SOM, the most pressing concern from both camps was the side effects, which are extensively documented in the medical literature [41-46].”
BackgroundQuantitative Prediction of Fold Resistance for Inhibitors of EGFR
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“Finally, while increased affinity for ATP (20) may be a contributor to resistance, the present results suggest that disruption of favorable”
InfluentialZhai, X., Ward, R. A., Doig, P. C., & Argyrou, A. (2020) · Biochemistry · doi:10.1021/acs.biochem.0c00104 · Cited by 84
The ErbB kinase domain: Structural perspectives into kinase activation and inhibition
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“The crystal structure of HKI-272 bound to EGFR Thr766Met shows the kinase domain in an inactive structure with helix αC displaced outward, similar to the lapatinib-bound structure [72].”
BackgroundClinical perspectives for irreversible tyrosine kinase inhibitors in cancer
Carmi, C., Mor, M., Petronini, P. G., & Alfieri, R. R. (2012) · Biochemical Pharmacology · doi:10.1016/j.bcp.2012.07.031 · Cited by 76
“conversion of gatekeeper threonine 790 to methionine (T790M), is the most common mechanism of acquired resistance to reversible tyrosine kinase inhibitors [26].”
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“Such enhancement of EGFR phosphorylation and activity by T790M in double mutants has also been showed by other researchers (34, 35).”
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“Therefore, another potential mechanism is suggested by the observation that the T790M mutation restores the ATP affinity of the mutant kinase to near wild-type levels in the L858R/T790M double mutant.(38) Because TKIs like gefitinib must compete with ATP for binding to the kinase active site, enhanced ATP affinity wou…”
BackgroundEGFR mutations as a prognostic and predictive marker in non-small-cell lung cancer
Wang, Z., & Fang, S. (2014) · Drug Design Development and Therapy · doi:10.2147/dddt.s69690 · Cited by 80
“T790M mutation abolishes the influence of EGFR-TKIs by increasing the affinity for adenosine triphosphate (ATP).(87) There is a major clinical problem in that NSCLC patients with EGFR mutations achieve acquired resistance after treatment with EGFR-TKIs.”
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EGFR T790M resistance mutation in non small-cell lung carcinoma
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“Inhibition of EGFR signaling in lapatinib-resistant non-small lung cancer (NCI-H1975) cells harboring T790M mutation Drug resistance is a critical and frequently encountered issue in cancer therapy, and T790M mutation in EGFR has been reported to contribute to lapatinib, gefitinib and erlotinib resistance [29].”
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KinaseMD: kinase mutations and drug response database
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“As in literature, mutations in these four kinds of substructure regions impact protein conformation changes (50–52), and these changes can result in drug response variation (53) and kinase dysfunction (54).”
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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