The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.
Novel mutant-selective EGFR kinase inhibitors against EGFR T790M
Open accessAbstract
The clinical efficacy of epidermal growth factor receptor (EGFR) kinase inhibitors in EGFR-mutant non-small-cell lung cancer (NSCLC) is limited by the development of drug-resistance mutations, including the gatekeeper T790M mutation. Strategies targeting EGFR T790M with irreversible inhibitors have had limited success and are associated with toxicity due to concurrent inhibition of wild-type EGFR. All current EGFR inhibitors possess a structurally related quinazoline-based core scaffold and were identified as ATP-competitive inhibitors of wild-type EGFR. Here we identify a covalent pyrimidine EGFR inhibitor by screening an irreversible kinase inhibitor library specifically against EGFR T790M. These agents are 30- to 100-fold more potent against EGFR T790M, and up to 100-fold less potent against wild-type EGFR, than quinazoline-based EGFR inhibitors in vitro. They are also effective in murine models of lung cancer driven by EGFR T790M. Co-crystallization studies reveal a structural basis for the increased potency and mutant selectivity of these agents. These mutant-selective irreversible EGFR kinase inhibitors may be clinically more effective and better tolerated than quinazoline-based inhibitors. Our findings demonstrate that functional pharmacological screens against clinically important mutant kinases represent a powerful strategy to identify new classes of mutant-selective kinase inhibitors.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“In 2009, Pasi et al. identified a series of covalent pyrimidine EGFR inhibitors, including WZ 3146, WZ 4002, and WZ 8040, through screening a library of irreversible kinase inhibitors specific to EGFRT790M.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [203]
In the citing paper
“These agents are designed to specifically inhibit mutant EGFR (ie, 19del-EGFR, L858R-EGFR and/or T790M+EGFR), sparing the WT receptor.14–18”
From Mechanisms of resistance to EGFR-targeted drugs: lung cancer (2016) · cites this paper as [14]
In the citing paper
“The presence of the T790M mutation was observed in approximately 50% of the cases in which biopsy was obtained at the time of relapse following gefitinib or erlotinib treatment in patients with the exon 19 deletion or the L858R EGFR mutation.”
From Mechanisms of resistance to EGFR-targeted drugs: lung cancer (2016) · cites this paper as [14]
In the citing paper
“AZD9291 has a distinct chemical structure from the other third-generation TKIs, WZ4002 (34) and CO-1686 (35).”
From AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer (2014) · cites this paper as [34]
In the citing paper
“C797 is located opposite T790 in the ATP binding pocket and forms a covalent bond with all third-generation TKIs and is necessary for the inhibitor to suppress EGFR (21).”
In the citing paper
“This approach has previously led to identification of clinically relevant drug resistance mutations to EGFR TKIs (30, 31).”
From Response Heterogeneity of EGFR and HER2 Exon 20 Insertions to Covalent EGFR and HER2 Inhibitors (2017) · cites this paper as [30]
In the citing paper
“Thus, the T790M structural alteration in essence “enabled” discovery of inhibitors that selectively inhibit T790M–bearing mutants, when in association with L858R or exon 19 deletions, relative to WT EGFR 58,59.”
From Structural, Biochemical, and Clinical Characterization of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer (2013) · cites this paper as [58]
In the citing paper
“Examination of the crystal structure of WZ4002 in complex with EGFR T790M (14) reveals that both L718 and L844 are in direct contact with the inhibitor; L718 primarily with the aniline ring and L844 with the pyrimidine ring (Figure 2A).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [14]
In the citing paper
“Cysteine 797 is the site of covalent binding for all three of these agents (14–16).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [14]
In the citing paper
“They are not only more potent on EGFR T790M, but also selectively inhibit mutant over WT EGFR and hence should lead to increased clinical efficacy and less toxicity compared with afatinib (14–16).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [14]
In the citing paper
“C797 is the site of covalent binding of WZ4002 and previously demonstrated to lead to drug resistance if mutated to serine (14).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [14]
In the citing paper
“CO-1686 is structurally more closely related to WZ4002 than to AZD9291 and in all of the models tested CO-1686 is very similar in vitro to WZ4002 (14–16).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [14]
In the citing paper
“However, ENU mutagenesis studies have been predictive of clinical drug resistance mutations in several prior studies (14, 24).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [14]
In the citing paper
“In prior studies, introduction of C797S into the background of EGFR L858R/T790M or EGFR Del 19/T790M resulted in significant loss of cellular potency for WZ4002 (14).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [14]
In the citing paper
“Analogously, a non-covalent analogue of WZ4002, WZ4003, was ineffective in in vitro models of EGFR T790M (14).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [14]
In the citing paper
“These include the development of mutant selective EGFR kinase inhibitors, including WZ4002, CO-1686 and AZD9291, which to date have demonstrated encouraging efficacy in both preclinical models and in EGFR mutant NSCLC patients with EGFR T790M mediated drug resistance (14–18).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [14]
In the citing paper
“WZ4002 is a covalent pyrimidine EGFR inhibitor specifically designed against EGFR T790M that is 30–100 fold more potent against EGFR T790M, and up to 100 fold less potent against wild type EGFR than quinazoline based EGFR inhibitors in vitro and is effective in murine models of lung cancer driven by EGFR T790M [84].”
From A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): Old successes and future perspectives (2015) · cites this paper as [84]
In the citing paper
“Both 2G and 3G EGFR‐TKI are irreversible small‐molecule inhibitors that covalently bind to EGFR kinase by targeting the cysteine‐797 residue, located in the ATP binding pocket, and 3G EGFR‐TKI are considered to be more specific for EGFR sensitizing mutations than 2G EGFR‐TKI.12, 13, 14”
In the citing paper
“A third generation of EGFR inhibitors followed afatinib; these covalent inhibitors selectively target the T790M mutant over wild-type EGFR, and include WZ4002 (Dana–Farber Cancer Institute)43, osimertinib44,45 and rociletinib (Clovis Oncology; CO-1686)46 (Fig. 2c).”
From Advances in covalent drug discovery (2022) · cites this paper as [43]
In the citing paper
“Standard of care is rapidly changing with the development of third-generation, mutant-selective EGFR-TKIs that have activity against cells that harbor TKI-sensitive EGFR mutations. Unlike conventional EGFR-TKIs, this activity is maintained in the presence of T790M resistance mutation.8,9”
From Association Between Plasma Genotyping and Outcomes of Treatment With Osimertinib (AZD9291) in Advanced Non–Small-Cell Lung Cancer (2016) · cites this paper as [9]
In the citing paper
“Next-generation EGFR TKIs have since been developed specifically to target the T790M mutation, 17,18 and they have demonstrated high and durable responses in patients with advanced EGFRmutant NSCLC who have been previously treated and in whom firstor second-generation EGFR TKIs have failed.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma
Mok, T. S., Wu, Y.-L., Thongprasert, S., Yang, C.-H., Chu, D.-T., Saijo, N., Sunpaweravong, P., Han, B., Margono, B., Ichinose, Y., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0810699 · Cited by 8,261
MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling
Engelman, J. A., Zejnullahu, K., Mitsudomi, T., Song, Y., Hyland, C., Park, J. O., Lindeman, N., Gale, C.-M., Zhao, X., Christensen, J., et al. (2007) · Science · doi:10.1126/science.1141478 · Cited by 4,496
EGFR Mutation and Resistance of Non–Small-Cell Lung Cancer to Gefitinib
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
Self-citationPao, 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
Screening for Epidermal Growth Factor Receptor Mutations in Lung Cancer
Rosell, R., Moran, T., Queralt, C., Porta, R., Cardenal, F., Camps, C., Majem, M., Lopez-Vivanco, G., Isla, D., Provencio, M., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0904554 · Cited by 2,373
The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP
Yun, C.-H., Mengwasser, K. E., Toms, A. V., Woo, M. S., Greulich, H., Wong, K.-K., Meyerson, M., & Eck, M. J. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0709662105 · Cited by 2,118
Self-citationBIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models
Li, D., Ambrogio, L., Shimamura, T., Kubo, S., Takahashi, M., Chirieac, L. R., Padera, R. F., Shapiro, G. I., Baum, A., Himmelsbach, F., et al. (2008) · Oncogene · doi:10.1038/onc.2008.109 · Cited by 1,447
Self-citationDiscovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity
Tsai, J., Lee, J. T., Wang, W., Zhang, J., Cho, H., Mamo, S., Bremer, R., Gillette, S., Kong, J., Haass, N. K., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0711741105 · Cited by 1,346
Yun, C.-H., Boggon, T. J., Li, Y., Woo, M. S., Greulich, H., Meyerson, M., & Eck, M. J. (2007) · Cancer Cell · doi:10.1016/j.ccr.2006.12.017 · Cited by 1,192
Self-citationEngelman, J. A., Zejnullahu, K., Gale, C.-M., Lifshits, E., Gonzales, A. J., Shimamura, T., Zhao, F., Vincent, P. W., Naumov, G. N., Bradner, J. E., et al. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-1885 · Cited by 730
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Items 101–200 of 1,000
Nan, X., Xie, C., Yu, X., & Liu, J. (2017) · Oncotarget · doi:10.18632/oncotarget.20095 · Cited by 203
Chen, Z., Sasaki, T., Tan, X., Carretero, J., Shimamura, T., Li, D., Xu, C., Wang, Y., Adelmant, G., Capelletti, M., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-1671 · Cited by 195
Self-citationPrecision Oncology: The Road Ahead
Senft, D., Leiserson, M. D. M., Ruppin, E., & Ronai, Z. A. (2017) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2017.08.003 · Cited by 199
El‐Metwally, S. A., Saied, K. F., Eissa, I. H., & Elkaeed, E. B. (2019) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2019.102944 · Cited by 191
Gonzalvez, F., Vincent, S., Baker, T. E., Gould, A. E., Li, S., Wardwell, S. D., Nadworny, S., Ning, Y., Zhang, S., Huang, W.-S., et al. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-1683 · Cited by 190
Self-citationOncogenic mutant forms of EGFR: Lessons in signal transduction and targets for cancer therapy
Pines, G., Köstler, W. J., & Yarden, Y. (2010) · FEBS Letters · doi:10.1016/j.febslet.2010.04.019 · Cited by 199
Mechanisms of drug resistance in kinases
Barouch‐Bentov, R., & Sauer, K. (2011) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2011.546344 · Cited by 192
Lung Cancer in the Era of Precision Medicine
Politi, K. A., & Herbst, R. S. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-2748 · Cited by 190
Minari, R., Bordi, P., & Tiseo, M. (2016) · Translational Lung Cancer Research · doi:10.21037/tlcr.2016.12.02 · Cited by 186
Cortot, A. B., Repellin, C. E., Shimamura, T., Capelletti, M., Zejnullahu, K., Ercan, D., Christensen, J. G., Wong, K.-K., Gray, N. S., & Jänne, P. A. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-2066 · Cited by 185
Self-citationCombination Osimertinib and Gefitinib in C797S and T790M EGFR-Mutated Non–Small Cell Lung Cancer
Arulananda, S., Do, H., Musafer, A., Mitchell, P., Dobrovic, A., & John, T. (2017) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2017.08.006 · Cited by 184
Acquired MET D1228V Mutation and Resistance to MET Inhibition in Lung Cancer
Bahcall, M., Sim, T., Paweletz, C. P., Patel, J. D., Alden, R. S., Kuang, Y., Sacher, A. G., Kim, N. D., Lydon, C., Awad, M. M., et al. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0686 · Cited by 183
The EGFR T790M Mutation in Acquired Resistance to an Irreversible Second-Generation EGFR Inhibitor
Kim, Y.-W., Ko, J., Cui, Z.-Y., Abolhoda, A., Ahn, J. S., Ou, S.-H., Ahn, M., & Park, K. (2012) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-11-0750 · Cited by 179
Tan, L., Wang, J., Tanizaki, J., Huang, Z., Aref, A. R., Rusan, M., Zhu, S.-J., Zhang, Y., Ercan, D., Liao, R. G., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1403438111 · Cited by 178
Self-citationTargeted covalent drugs of the kinase family
Singh, J., Petter, R. C., & Kluge, A. F. (2010) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2010.06.168 · Cited by 177
Sogabe, S., Kawakita, Y., Igaki, S., Iwata, H., Miki, H., Cary, D. R., Takagi, T., Takagi, S., Ohta, Y., & Ishikawa, T. (2012) · ACS Medicinal Chemistry Letters · doi:10.1021/ml300327z · Cited by 175
Lu, X., Yu, L., Zhang, Z., Ren, X., Smaill, J. B., & Ding, K. (2018) · Medicinal Research Reviews · doi:10.1002/med.21488 · Cited by 173
Russo, A., Franchina, T., Rita Ricciardi, G. R., Picone, A., Ferraro, G., Zanghì, M., Toscano, G., Giordano, A., & Adamo, V. (2015) · Oncotarget · doi:10.18632/oncotarget.4254 · Cited by 173
Chemical ‘omics’ approaches for understanding protein cysteine oxidation in biology
Leonard, S. E., & Carroll, K. S. (2010) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2010.11.012 · Cited by 172
Emerging strategies to overcome resistance to third-generation EGFR inhibitors
Shi, K., Wang, G., Pei, J., Zhang, J., Wang, J., Ouyang, L., Wang, Y., & Li, W. (2022) · Journal of Hematology & Oncology · doi:10.1186/s13045-022-01311-6 · Cited by 174
Patel, H., Pawara, R., Ansari, A., & Surana, S. (2017) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2017.05.027 · Cited by 170
To, C., Beyett, T. S., Jang, J., Feng, W. W., Bahcall, M., Haikala, H. M., Shin, B. H., Heppner, D. E., Rana, J. K., Leeper, B. A., et al. (2022) · Nature Cancer · doi:10.1038/s43018-022-00351-8 · Cited by 176
Self-citationChen, L., Fu, W., Zheng, L., Liu, Z., & Liang, G. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b01310 · Cited by 169
Self-citationHirano, T., Yasuda, H., Tani, T., Hamamoto, J., Oashi, A., Ishioka, K., Arai, D., Nukaga, S., Miyawaki, M., Kawada, I., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.5887 · Cited by 165
Buonato, J. M., & Lazzara, M. J. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-4721 · Cited by 163
Molecular mechanisms of resistance in epidermal growth factor receptor-mutant lung adenocarcinomas
Cortot, A. B., & Jänne, P. A. (2014) · European Respiratory Review · doi:10.1183/09059180.00004614 · Cited by 158
Self-citationStructure-Based Virtual Screening Approach for Discovery of Covalently Bound Ligands
Warshaviak, D. T., Golan, G., Borrelli, K. W., Zhu, K., & Kalid, O. (2014) · Journal of Chemical Information and Modeling · doi:10.1021/ci500175r · Cited by 156
Ricordel, C., Friboulet, L., Facchinetti, F., & Soria, J. (2017) · Annals of Oncology · doi:10.1093/annonc/mdx705 · Cited by 156
Soucheray, M., Capelletti, M., Pulido, I., Kuang, Y., Paweletz, C. P., Becker, J. H., Kikuchi, E., Xu, C., Patel, T. B., Al‐Shahrour, F., et al. (2015) · Cancer Research · doi:10.1158/0008-5472.can-15-0377 · Cited by 157
Self-citationUncommon EGFR mutations in advanced non-small cell lung cancer
O'Kane, G. M., Bradbury, P. A., Feld, R. D., Leighl, N. B., Liu, G., Pisters, K.-M., Kamel‐Reid, S., Tsao, M., & Shepherd, F. A. (2017) · Lung Cancer · doi:10.1016/j.lungcan.2017.04.016 · Cited by 153
Ichihara, E., Westover, D., Meador, C. B., Yan, Y., Bauer, J. A., Lu, P., Ye, F., Kulick, A., de Stanchina, E., McEwen, R., et al. (2017) · Cancer Research · doi:10.1158/0008-5472.can-16-2300 · Cited by 150
EGFR Exon 19 Insertions: A New Family of Sensitizing EGFR Mutations in Lung Adenocarcinoma
He, M., Capelletti, M., Nafa, K., Yun, C.-H., Arcila, M. E., Miller, V. A., Ginsberg, M. S., Zhao, B., Kris, M. G., Eck, M. J., et al. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-2361 · Cited by 149
Self-citationBinding mode of the breakthrough inhibitor AZD9291 to epidermal growth factor receptor revealed
Yosaatmadja, Y., Silva, S., Dickson, J. M. J. J., Patterson, A. V., Smaill, J. B., Flanagan, J. U., McKeage, M. J., & Squire, C. J. (2015) · Journal of Structural Biology · doi:10.1016/j.jsb.2015.10.018 · Cited by 150
Mechanism for activation of mutated epidermal growth factor receptors in lung cancer
Brewer, M. R., Yun, C., Lai, D., Lemmon, M. A., Eck, M. J., & Pao, W. J. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1220050110 · Cited by 152
Self-citationUSP8 Is a Novel Target for Overcoming Gefitinib Resistance in Lung Cancer
Byun, S., Lee, S., Lee, J., Jeong, C., Farrand, L., Lim, S., Reddy, K., Kim, J. Y., Lee, M., Lee, H. J., et al. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-3696 · Cited by 147
Liao, B.-C., Lin, C., & Yang, J. C. (2015) · Current Opinion in Oncology · doi:10.1097/cco.0000000000000164 · Cited by 149
Discovery of Cysteine-targeting Covalent Protein Kinase Inhibitors
Lu, X., Smaill, J. B., Patterson, A. V., & Ding, K. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c01719 · Cited by 147
Reckamp, K. L., Giaccone, G., Camidge, D. R., Gadgeel, S. M., Khuri, F. R., Engelman, J. A., Koczywas, M., Rajan, A., Campbell, A. K., Gernhardt, D., et al. (2014) · Cancer · doi:10.1002/cncr.28561 · Cited by 144
Peng, Y.-H., Shiao, H., Tu, C., Liu, P.-M., Hsu, J. T.-A., Amancha, P. K., Wu, J., Coumar, M. S., Chen, C.-H., Wang, S.-Y., et al. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm400072p · Cited by 144
Structural Insight and Development of EGFR Tyrosine Kinase Inhibitors
Amelia, T., Kartasasmita, R. E., Ohwada, T., & Tjahjono, D. H. (2022) · Molecules · doi:10.3390/molecules27030819 · Cited by 149
Differential Sensitivity of ERBB2 Kinase Domain Mutations towards Lapatinib
Kancha, R. K., von Bubnoff, N. C. C., Bartosch, N., Peschel, C., Engh, R. A., & Duyster, J. (2011) · PLoS ONE · doi:10.1371/journal.pone.0026760 · Cited by 140
Yoshikawa, S., Kukimoto-Niino, M., Parker, L., Handa, N., Terada, T., Fujimoto, T., Terazawa, Y., Wakiyama, M., Sato, M., Sano, S., et al. (2013) · Oncogene · doi:10.1038/onc.2012.21 · Cited by 138
Self-citationCovalent inhibitors: an opportunity for rational target selectivity
Lagoutte, R., Patouret, R., & Winssinger, N. (2017) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2017.05.008 · Cited by 138
25 Years of Small Molecular Weight Kinase Inhibitors: Potentials and Limitations
Fabbro, D. (2014) · Molecular Pharmacology · doi:10.1124/mol.114.095489 · Cited by 141
Molecularly Targeted Therapies in Non–Small-Cell Lung Cancer Annual Update 2014
Morgensztern, D., Campo, M. J., Dahlberg, S. E., Doebele, R. C., Garon, E. B., Gerber, D. E., Goldberg, S. B., Hammerman, P. S., Heist, R. S., Hensing, T. A., et al. (2015) · Journal of Thoracic Oncology · doi:10.1097/jto.0000000000000405 · Cited by 138
Remón, J., Morán, T., Majem, M., Reguart, N., Dalmau, E., Márquez-Medina, D., & LIANES, P. (2013) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2013.06.002 · Cited by 137
Ouyang, X., Zhou, S., Su, C. T. T., Ge, Z., Li, R., & Kwoh, C. K. (2013) · Journal of Computational Chemistry · doi:10.1002/jcc.23136 · Cited by 134
A Structure-Guided Approach to Creating Covalent FGFR Inhibitors
Zhou, W., Hur, W., McDermott, U., Dutt, A., Xian, W., Ficarro, S. B., Zhang, J., Sharma, S. V., Brugge, J. S., Meyerson, M. M., et al. (2010) · Chemistry & Biology · doi:10.1016/j.chembiol.2010.02.007 · Cited by 135
Self-citationResponse Heterogeneity of EGFR and HER2 Exon 20 Insertions to Covalent EGFR and HER2 Inhibitors
Kosaka, T., Tanizaki, J., Paranal, R. M., Endoh, H., Lydon, C., Capelletti, M., Repellin, C. E., Choi, J., Ogino, A., Calles, A., et al. (2017) · Cancer Research · doi:10.1158/0008-5472.can-16-3404 · Cited by 131
Self-citationTargeting non-small cell lung cancer with small-molecule EGFR tyrosine kinase inhibitors
Singh, M., & Jadhav, H. R. (2017) · Drug Discovery Today · doi:10.1016/j.drudis.2017.10.004 · Cited by 131
Kosaka, T., Yamaki, E., Mogi, A., & Kuwano, H. (2011) · BioMed Research International · doi:10.1155/2011/165214 · Cited by 130
EGFR-mutated oncogene-addicted non-small cell lung cancer: Current trends and future prospects
Soria, J., Mok, T. S. K., Cappuzzo, F., & Janne, P. A. (2011) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2011.10.003 · Cited by 131
Structural Basis of AZD9291 Selectivity for EGFR T790M
Yan, X.-E., Ayaz, P., Zhu, S., Zhao, P., Liang, L., Zhang, C. H., Wu, Y.-C., Li, J.-L., Choi, H. G., Huang, X., et al. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00891 · Cited by 129
Self-citationSuppression of Adaptive Responses to Targeted Cancer Therapy by Transcriptional Repression
Rusan, M., Li, K., Li, Y. Y., Christensen, C. L., Abraham, B. J., Kwiatkowski, N. P., Buczkowski, K. A., Bockorny, B., Chen, T., Li, S., et al. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-17-0461 · Cited by 128
Self-citationOvercoming Cancer Drug Resistance Utilizing PROTAC Technology
Burke, M. R., Smith, A. R., & Zheng, G. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.872729 · Cited by 129
Jung, S. K., Lee, M., Lim, D. Y., Kim, J., Singh, P., Lee, S., Jeong, C., Lim, T., Chen, H., Chi, Y., et al. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.585513 · Cited by 125
Epidermal growth factor receptor (EGFR) mutations in lung cancer: preclinical and clinical data
Jorge, S. E., Kobayashi, S. S., & Costa, D. B. (2014) · Brazilian Journal of Medical and Biological Research · doi:10.1590/1414-431x20144099 · Cited by 127
Fighting cancer drug resistance: Opportunities and challenges for mutation-specific EGFR inhibitors
Juchum, M., Günther, M., & Laufer, S. (2015) · Drug Resistance Updates · doi:10.1016/j.drup.2015.05.002 · Cited by 126
Development of Selective Covalent Janus Kinase 3 Inhibitors
Tan, L., Akahane, K., McNally, R., Reyskens, K. M. S. E., Ficarro, S. B., Liu, S., Herter-Sprie, G. S., Koyama, S., Pattison, M. J., Labella, K., et al. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b00710 · Cited by 122
Self-citationHow Genetically Engineered Mouse Tumor Models Provide Insights Into Human Cancers
Politi, K. A., & Pao, W. J. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2010.30.8304 · Cited by 126
Buettner, R., Wolf, J., & Thomas, R. K. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.45.9867 · Cited by 123
Sun, J., Ahn, M., Choi, Y., Ahn, J. S., & Park, K. (2013) · Lung Cancer · doi:10.1016/j.lungcan.2013.08.023 · Cited by 121
Epidermal Growth Factor Receptor Inhibition in Lung Cancer: Status 2012
Hirsch, F. R., Janne, P. A., Eberhardt, W., Cappuzzo, F., Thatcher, N., Pirker, R., Choy, H., Kim, E. S., Paz-Ares, L. G., Gandara, D. R., et al. (2013) · Journal of Thoracic Oncology · doi:10.1097/jto.0b013e31827ed0ff · Cited by 122
Cho, J., Chen, L., Sangji, N., Okabe, T., Yonesaka, K., Francis, J. M., Flavin, R. J., Johnson, W., Kwon, J., Yu, S., et al. (2013) · Cancer Research · doi:10.1158/0008-5472.can-13-1145 · Cited by 117
Self-citationEmerging Role of mTOR in the Response to Cancer Therapeutics
Ilagan, E., & Manning, B. D. (2016) · Trends in cancer · doi:10.1016/j.trecan.2016.03.008 · Cited by 118
Choudhury, N. J., Marra, A., Sui, J. S. Y., Flynn, J. R., Yang, S., Falcon, C. J., Selenica, P., Schoenfeld, A. J., Rekhtman, N., Gomez, D. R., et al. (2022) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2022.11.022 · Cited by 123
Gadgeel, S. M., & Wozniak, A. J. (2013) · Clinical Lung Cancer · doi:10.1016/j.cllc.2012.12.001 · Cited by 116
Targeting Drug Resistance in EGFR with Covalent Inhibitors: A Structure-Based Design Approach
Engel, J., Richters, A., Getlik, M., Tomassi, S., Keul, M., Termathe, M., Lategahn, J., Becker, C., Mayer‐Wrangowski, S. C., Grütter, C., et al. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b01082 · Cited by 114
Strategies for modern biomarker and drug development in oncology
Smith, A. D., Roda, D., & Yap, T. A. (2014) · Journal of Hematology & Oncology · doi:10.1186/s13045-014-0070-8 · Cited by 112
EGFR G796D mutation mediates resistance to osimertinib
Zheng, D., Hu, M., Bai, Y., Zhu, X., Lu, X., Wu, C., Wang, J., Liu, L., Wang, Z., Ni, J., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.17913 · Cited by 111
Massarelli, E., Johnson, F. M., Erickson, H. S., Wistuba, I. I., & Papadimitrakopoulou, V. (2013) · Lung Cancer · doi:10.1016/j.lungcan.2013.01.018 · Cited by 110
Third generation EGFR TKIs in EGFR-mutated NSCLC: Where are we now and where are we going
Russo, A., Franchina, T., Ricciardi, G. R. R., Smiroldo, V., Picciotto, M., Zanghì, M., Rolfo, C. D., & Adamo, V. (2017) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2017.07.003 · Cited by 112
Song, Z., Yang, G., Wang, C., Huang, S., Shu, X. H., Liu, K., Zhou, Y., & Ma, X. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b00840 · Cited by 110
Günther, M., Lategahn, J., Juchum, M., Döring, E., Keul, M., Engel, J., Tumbrink, H. L., Rauh, D., & Laufer, S. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b00316 · Cited by 108
Pyrimidine-based EGFR TK inhibitors in targeted cancer therapy
Ayati, A., Moghimi, S., Toolabi, M., & Foroumadi, A. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113523 · Cited by 107
Yoshida, T., Zhang, G., Smith, M. A., Lopez, A. S., Bai, Y., Li, J., Fang, B., Koomen, J. M., Rawal, B., Fisher, K. J., et al. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-1559 · Cited by 106
Reita, D., Pabst, L., Pencreach, E., Guérin, É., Dano, L., Rimelen, V., Voegeli, A., Vallat, L. D., Mascaux, C., & Beau‐Faller, M. (2021) · Cancers · doi:10.3390/cancers13194926 · Cited by 107
Tan, C.-S., Cho, B.-C., & Soo, R. A. (2016) · Lung Cancer · doi:10.1016/j.lungcan.2016.01.003 · Cited by 105
Doucey, M., & Carrara, S. (2018) · Trends in biotechnology · doi:10.1016/j.tibtech.2018.07.014 · Cited by 107
Xu, L., Kikuchi, E., Xu, C., Ebi, H., Ercan, D., Cheng, K. A., Padera, R. F., Engelman, J. A., Janne, P. A., Shapiro, G. I., et al. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-3720 · Cited by 106
Self-citation20 years since the approval of first EGFR-TKI, gefitinib: Insight and foresight
Singh, S. K., Sadhukhan, S., & Sonawane, A. (2023) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2023.188967 · Cited by 109
Masui, K., Gini, B., Wykosky, J., Zanca, C., Mischel, P. S., Furnari, F. B., & Cavenee, W. K. (2013) · Carcinogenesis · doi:10.1093/carcin/bgt086 · Cited by 111
An Overview of EGFR Mechanisms and Their Implications in Targeted Therapies for Glioblastoma
Rodriguez, S. M. B., Kamel, A. E., Ciubotaru, G. V., Onose, G., Sevastre, A.-S., Sfredel, V., Dănoiu, S., Dricu, A., & Tătăranu, L. G. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241311110 · Cited by 108
The Genomics of Lung Adenocarcinoma: Opportunities for Targeted Therapies
Greulich, H. E. (2010) · Genes & Cancer · doi:10.1177/1947601911407324 · Cited by 109
Günther, M., Juchum, M., Kelter, G., Fiebig, H. H., & Laufer, S. (2016) · Angewandte Chemie International Edition · doi:10.1002/anie.201603736 · Cited by 102
Osimertinib in the treatment of non-small-cell lung cancer: design, development and place in therapy
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
Discovery 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-citationSelective Antitumor Activity of Ibrutinib in EGFR-Mutant Non–Small Cell Lung Cancer Cells
Gao, W., Wang, M. L., Wang, L., Lu, H., Wu, S., Dai, B., Ou, Z., Zhang, L., Heymach, J. V., Gold, K. A., et al. (2014) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/dju204 · Cited by 101
A covalently bound inhibitor triggers EZH2 degradation through CHIP‐mediated ubiquitination
Wang, X., Cao, W., Zhang, J., Yan, M., Xu, Q., Wu, X., Wan, L., Zhang, Z., Zhang, C., Qin, X., et al. (2017) · The EMBO Journal · doi:10.15252/embj.201694058 · Cited by 100
Molecular basis for cooperative binding and synergy of ATP-site and allosteric EGFR inhibitors
Beyett, T. S., To, C., Heppner, D. E., Rana, J. K., Schmoker, A. M., Jang, J., Clercq, D. J. H. D., Gómez, G., Scott, D. A., Gray, N. S., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-30258-y · Cited by 104
Self-citationChhouri, H., Alexandre, D., & Grumolato, L. (2023) · Cancers · doi:10.3390/cancers15020504 · Cited by 103
The rise and fall of gatekeeper mutations? The BCR‐ABL1 T315I paradigm
Gibbons, D. L., Pricl, S., Kantarjian, H. M., Cortes, J. E., & Quintás‐Cardama, A. (2011) · Cancer · doi:10.1002/cncr.26225 · Cited by 101
Second-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Lung Cancers
Yu, H. A., & Riely, G. J. (2013) · Journal of the National Comprehensive Cancer Network · doi:10.6004/jnccn.2013.0024 · Cited by 99
Yeh, H. H., Ogawa, K., Balatoni, J., Mukhapadhyay, U., Pal, A., González-Lepera, C., Shavrin, A., Soghomonyan, S., Flores, L. G., Young, D. P., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1010744108 · Cited by 98
Planken, S., Behenna, D. C., Nair, S. K., Johnson, T. O., Nagata, A., Almaden, C., Bailey, S., Ballard, T. E., Bernier, L., Cheng, H., et al. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b01894 · Cited by 97
Wu, L., Ke, L., Zhang, Z., Yu, J., & Meng, X. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.602762 · Cited by 99
Cheng, H., Nair, S. K., Murray, B. W., Almaden, C., Bailey, S., Baxi, S. M., Behenna, D. C., Cho-Schultz, S., Dalvie, D., Dinh, D. M., et al. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b01633 · Cited by 98
Mechanisms of resistance to third-generation EGFR tyrosine kinase inhibitors
Wang, S., Song, Y., Yan, F., & Liu, D. (2016) · Frontiers of Medicine · doi:10.1007/s11684-016-0488-1 · Cited by 96
Lelais, G., Epple, R., Marsilje, T. H., Long, Y. O., McNeill, M., Chen, B., Lu, W., Anumolu, J., Badiger, S., Bursulaya, B., et al. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b01985 · Cited by 95
Covalent targeting of acquired cysteines in cancer
Visscher, M., Arkin, M. R., & Dansen, T. B. (2016) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2015.11.004 · Cited by 95
Metadata
- Authors
- Zhou, W., Ercan, D., Chen, L., Yun, C.-H., Li, D., Capelletti, M., Cortot, A. B., Chirieac, L., Iacob, R. E., Padera, R., Engen, J. R., Wong, K.-K., Eck, M. J., Gray, N. S., & Jänne, P. A.
- Affiliations
- Dana-Farber Cancer Institute (US)
- Brigham and Women's Hospital (US)
- Northeastern University (US)
- Corresponding author
- Gray, Nathanael S.
- ORCID
- Venue
- Nature
- Published
- 2009-12
- Volume
- 462
- Issue
- 7276
- Pages
- 1070-1074
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2879581
- OpenAlex
- W2133963438
- Cited by
- 1,013
- References
- 30
- Citations by year
- 2026: 32 · 2025: 43 · 2024: 39 · 2023: 60 · 2022: 46 · 2021: 55 · 2020: 62 · 2019: 55 · 2018: 66 · 2017: 84 · 2016: 82 · 2015: 75 · 2014: 71 · 2013: 82 · 2012: 54
- FWCI
- 45.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute on Aging (R01AG2400401)
- National Cancer Institute (R01CA116020, R01CA122794, R01CA130876, R01CA11446, P50CA090578, R01CA135257, R01CA080942)
- National Institute of General Medical Sciences (R01GM070590)
- 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
- EGFR kinase inhibitors, mutant-selective inhibitors, irreversible kinase inhibitors, non-small cell lung cancer, drug resistance, co-crystallization, gatekeeper mutation
- MeSH terms
- Animals, Antineoplastic Agents, Drug Evaluation, Preclinical, Lung, Models, Chemical, Models, Molecular, Mutation, Phosphorylation, Drug Resistance, Neoplasm, NIH 3T3 Cells, Cell Line, Tumor, Protein Kinase Inhibitors, Cell Proliferation, Mice, ErbB Receptors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
