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Structures of Lung Cancer-Derived EGFR Mutants and Inhibitor Complexes: Mechanism of Activation and Insights into Differential Inhibitor Sensitivity
Open accessAbstract
Mutations in the EGFR kinase are a cause of non-small-cell lung cancer. To understand their mechanism of activation and effects on drug binding, we studied the kinetics of the L858R and G719S mutants and determined their crystal structures with inhibitors including gefitinib, AEE788, and a staurosporine. We find that the mutations activate the kinase by disrupting autoinhibitory interactions, and that they accelerate catalysis as much as 50-fold in vitro. Structures of inhibitors in complex with both wild-type and mutant kinases reveal similar binding modes for gefitinib and AEE788, but a marked rotation of the staurosporine in the G719S mutant. Strikingly, direct binding measurements show that gefitinib binds 20-fold more tightly to the L858R mutant than to the wild-type enzyme.
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“The exquisite sensitivity of EGFR-L858R and exon 19 deletions to EGFR TKIs stems from two effects: their enhanced intrinsic affinity for these TKIs and their markedly decreased affinity for substrate ATP 38,39.”
From Structural, Biochemical, and Clinical Characterization of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer (2013) · cites this paper as [38]
In the citing paper
“Examination of the homology model of the inactive state suggests a mechanism of activation related to that of L858R 38.”
From Structural, Biochemical, and Clinical Characterization of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer (2013) · cites this paper as [38]
In the citing paper
“Beyond this glycine, the conformation of the polypeptide chain is quite similar to that of the WT and L858R kinases 38”
From Structural, Biochemical, and Clinical Characterization of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer (2013) · cites this paper as [38]
In the citing paper
“EGFR mutations are expected to activate the EGFR by destabilizing the inactive form of EGFR without ligand stimulation [7–9].”
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BackgroundFDA-approved small-molecule kinase inhibitors
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“This mutation is believed to induce resistance by decreasing the Km for ATP thereby increasing the concentration of inhibitor needed to efficiently inhibit signaling (Yun et al., 2007).”
Rare epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer
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“increased receptor dimerization and activity compared to WT [11,13,14].”
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Mechanism for Activation of the EGF Receptor Catalytic Domain by the Juxtamembrane Segment
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“Introduction of the L834R mutation, commonly found in lung cancer patients, increases the activity of the kinase core by $14-fold, consistent with previous results (Yun et al., 2007; Zhang et al., 2006) (Figure 2A).”
Yasuda, H., Park, E., Yun, C.-H., Sng, N. J., Lucena-Araujo, A. R., Yeo, W.-L., Huberman, M. S., Cohen, D. W., Nakayama, S., Ishioka, K., et al. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3007205 · Cited by 571
Self-citationOptimization of Dosing for EGFR-Mutant Non–Small Cell Lung Cancer with Evolutionary Cancer Modeling
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“It is unclear from the current crystallographic data and from our molecular dynamics simulations how acquisition of this mutation results in resistance to ATP-competitive EGFR inhibitors; there may be differential effects on ATP and small molecule binding, as seen for L858R and G719S mutations [57] or a shift in the c…”
BackgroundSelf-citationRoskoski, R. J. (2018) · Pharmacological Research · doi:10.1016/j.phrs.2018.11.014 · Cited by 502
ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation
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“EGFR-TKD structures are from PDB codes 2GS7 (5) and 2ITX (48).”
BackgroundEpidermal Growth Factor Receptor Tyrosine Kinase Inhibitor–Resistant Disease
Ohashi, K., Maruvka, Y. E., Michor, F., & Pao, W. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.43.3912 · Cited by 467
“that these mutants preferentially bind to drugs like gefitinib and erlotinib over ATP.(17,18) Other poten-”
BackgroundHalogen bonding (X‐bonding): A biological perspective
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Erlotinib binds both inactive and active conformations of the EGFR tyrosine kinase domain
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“It should be noted that these mutations destabilize the EGFR-TK conformation preferred by lapatinib (68), but stabilize the conformation bound by erlotinib (62), getitinib and other TKIs (71).”
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Single and Dual Targeting of Mutant EGFR with an Allosteric Inhibitor
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“EGFR Protein Expression and Purification Constructs spanning residues 696–1022 of human EGFR (including wild-type, L858R/T790M, L858R/T790M/C797S, and T790M/ V948R mutant sequences) were prepared in a His6 and GST-fusion double-tagged format using the pTriEX system (Novagen) for expression in Sf9 insect cells essentia…”
MethodSelf-citationMolecular Mechanisms of Disease-Causing Missense Mutations
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“interactions and considerably accelerated the catalysis [183].”
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The Juxtamembrane Region of the EGF Receptor Functions as an Activation Domain
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“However, in overlays of all known active and inactive EGFR TKD structures (including the structure described here), the positions of these three residues do not change.”
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Structure and Clinical Relevance of the Epidermal Growth Factor Receptor in Human Cancer
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Self-citationCatalytic Control in the EGF Receptor and Its Connection to General Kinase Regulatory Mechanisms
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“These mutations, such as Leu 834 to Arg, have been shown to activate the kinase, most likely by destabilization of the inactive CDK/Src-like conformation (Yun et al., 2007; Zhang et al., 2006).”
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The regulation of protein phosphorylation
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Classic and contemporary approaches to modeling biochemical reactionsPreprint
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“We will assume a catalytic rate constant of 10 2 sec 1, a value that is atypically slow for many metabolic enzymes, but reasonable for phosphorylation of peptide substrates by receptor kinases (Li et al. 2003; Yun et al. 2007, 2008).”
BackgroundAnnotating Cancer Variants and Anti-Cancer Therapeutics in Reactome
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“This mutation disrupts autoinhibitory interactions, facilitating adoption of an active conformation [63].”
BackgroundSmall Molecule Kinase Inhibitor Drugs (1995–2021): Medical Indication, Pharmacology, and Synthesis
Ayala-Aguilera, C. C., Valero, T., Lorente‐Macías, Á., Baillache, D. J., Croke, S., & Unciti‐Broceta, A. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c00963 · Cited by 294
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Predicting drug susceptibility of non–small cell lung cancers based on genetic lesions
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Self-citationProtein kinase inhibitors: contributions from structure to clinical compounds
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“As the work with the EGFR inhibitor gefitinib, Yun et al. (2007) has shown it is the balance between ATP affinity and drug affinity that determines the efficacy of the drug.”
BackgroundInfluentialChiu, C.-H., Yang, C.-T., Shih, J.-Y., Huang, M.-S., Su, W.-C., Lai, R.-S., Wang, C.-C., Hsiao, S.-H., Lin, Y.-C., Ho, C.-L., et al. (2015) · Journal of Thoracic Oncology · doi:10.1097/jto.0000000000000504 · Cited by 241
“Using a crystal structure analysis, Yun et al.19 showed that G719S mutant had a 50-fold weaker affinity to gefitinib than did L858R mutant.”
Riess, J. W., Gandara, D. R., Frampton, G. M., Madison, R., Peled, N., Bufill, J. A., Dy, G. K., Ou, S.-H. I., Stephens, P. J., McPherson, J. D., et al. (2018) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2018.06.019 · Cited by 240
“TMB intermediate high (10-20) 3325 (26) 82 (6.”
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Structural features of the protein kinase domain and targeted binding by small-molecule inhibitors
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“B, crystal structure of type I in 2ITY) (113).”
BackgroundEGFR T790M Mutation: A Double Role in Lung Cancer Cell Survival?
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“Depending on reaction conditions and choice of phosphoacceptor substrate, the measured Km[ATP] of the L858R mutant ranged from ~30 to 150 μM, roughly 5 to 30 times that of the WT enzyme [17,23].”
BackgroundInfluentialSelf-citationSos, M. L., Rode, H. B., Heynck, S., Peifer, M., Fischer, F., Klüter, S., Pawar, V. G., Reuter, C., Heuckmann, J. M., Weiss, J., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-3106 · Cited by 220
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InfluentialSelf-citationErbB/HER protein-tyrosine kinases: Structures and small molecule inhibitors
Roskoski, R. J. (2014) · Pharmacological Research · doi:10.1016/j.phrs.2014.06.001 · Cited by 226
Aptamer Therapeutics in Cancer: Current and Future
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“5 nM [5], while the Kd of cetuximab (Erbitux®, ImClone, Branchburg, NJ, USA), an inhibitory anti-EGFR antibody, is far smaller, 2.”
BackgroundStructure and Ubiquitination-Dependent Activation of TANK-Binding Kinase 1
Tu, D., Zhu, Z., Zhou, A. Y., Yun, C., Lee, K., Toms, A. V., Li, Y., Dunn, G. P., Chan, E. M., Thai, T. C., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.01.033 · Cited by 222
“In-vitro enzyme kinetics and other biophysical studies Kinase assays were carried out in triplicate using the ATP/NADH coupled assay system in a 96-well format as described (Yun et al., 2007).”
MethodSelf-citationActivation Mechanism of Oncogenic Deletion Mutations in BRAF, EGFR, and HER2
Foster, S. A., Whalen, D. M., Özen, A., Wongchenko, M. J., Yin, J., Yen, I., Schaefer, G., Mayfield, J. D., Chmielecki, J., Stephens, P. J., et al. (2016) · Cancer Cell · doi:10.1016/j.ccell.2016.02.010 · Cited by 217
“Charged substitutions of these residues disrupt the hydrophobically driven inactive conformation, shifting the conformational equilibrium toward the active conformation (Wan et al., 2004; Yun et al., 2007).”
BackgroundLiu, X., Wang, P., Zhang, C., & Ma, Z. (2017) · Oncotarget · doi:10.18632/oncotarget.16854 · Cited by 222
“EGFR gene is an oncogene-driven gene, tyrosine kinases (TK) active [13].”
BackgroundReceptor tyrosine kinases and cancer: oncogenic mechanisms and therapeutic approaches
Saraon, P., Pathmanathan, S., Snider, J. D., Lyakisheva, A., Wong, V., & Štagljar, I. (2021) · Oncogene · doi:10.1038/s41388-021-01841-2 · Cited by 215
“For instance, somatic mutations in the active site of the EGFR kinase domain occur in ~16% of NSCLC, with the most common events being the L858R missense mutation (40%) localized to the activation loop and in-frame exon 19 deletions (44%) [12].”
BackgroundWatanabe, S., Minegishi, Y., Yoshizawa, H., Maemondo, M., Inoue, A., Sugawara, S., Isobe, H., Harada, M., Ishii, Y., Gemma, A., et al. (2014) · Journal of Thoracic Oncology · doi:10.1097/jto.0000000000000048 · Cited by 204
“In vitro studies have indicated that the affinity of gefitinib for EGFR proteins with uncommon EGFR mutations is lower than the affinity of gefitinib for EGFR proteins with common EGFR mutations.(25) A sixfold or 14-fold higher concentration of gefitinib was required to inhibit the growth of cells expressing G719X or…”
ResultActivation of the EGF Receptor by Ligand Binding and Oncogenic Mutations: The “Rotation Model”
Purba, E. R., Saita, E., & MARUYAMA, I. N. (2017) · Cells · doi:10.3390/cells6020013 · Cited by 218
“G719 contributes to interactions that hold helix αC in the inactive conformation [130].”
BackgroundInsights into the Aberrant Activity of Mutant EGFR Kinase Domain and Drug Recognition
Gajiwala, K. S., Feng, J., Ferre, R. A., Ryan, K., Brodsky, O., Weinrich, S. L., Kath, J. C., & Stewart, A. (2012) · Structure · doi:10.1016/j.str.2012.11.014 · Cited by 204
“obtained by the soaking technique, showed (Stamos et al., 2002; Yun et al., 2007) and (2) the higher ATP Km value of the mutant enzyme relative to the WT (Yun et al.”
BackgroundMethodResultInfluentialStructure-guided development of affinity probes for tyrosine kinases using chemical genetics
Blair, J. A., Rauh, D., Kung, C. K.-H., Yun, C., Fan, Q.-W., Rode, H. B., Zhang, C., Eck, M. J., Weiss, W. A., & Shokat, K. M. (2007) · Nature Chemical Biology · doi:10.1038/nchembio866 · Cited by 204
Self-citationWang, S., Tsui, S. T., Liu, C., Song, Y., & Liu, D. (2016) · Journal of Hematology & Oncology · doi:10.1186/s13045-016-0290-1 · Cited by 208
“Since EGFR dimerization is required for kinase enzyme activation [22–24], the investigators hypothesized that”
BackgroundAbourehab, M. A. S., Alqahtani, A. M., Youssif, B. G. M., & Gouda, A. M. (2021) · Molecules · doi:10.3390/molecules26216677 · Cited by 211
“They also include the crystal structure of gefitinib bound to the mutated EGFR kinase (pdb: 2ITO, 2ITZ, 3UG2, 4I22, 5Y80, and 5Y7Z) [15,66,84,85].”
BackgroundPharmacological targeting of the pseudokinase Her3
Xie, T., Lim, S. M., Westover, K. D., Dodge, M. E., Ercan, D., Ficarro, S. B., Udayakumar, D., Gurbani, D., Tae, H. S., Riddle, S. M., et al. (2014) · Nature Chemical Biology · doi:10.1038/nchembio.1658 · Cited by 205
“This is also consistent with the fact that we do not observe a significant improvement in IC 50 under the conditions of our binding assay between our most potent non-covalent and covalent Her3 ligands.”
EGFR-mutated lung cancer: a paradigm of molecular oncology
Zhang, Z., Stiegler, A. L., Boggon, T. J., Kobayashi, S., & Halmos, B. (2010) · Oncotarget · doi:10.18632/oncotarget.186 · Cited by 197
Self-citationRedox Regulation of Epidermal Growth Factor Receptor Signaling through Cysteine Oxidation
Truong, T. H., & Carroll, K. S. (2012) · Biochemistry · doi:10.1021/bi301441e · Cited by 199
Ogino, A., Kitao, H., Hirano, S., Uchida, A., Ishiai, M., Kozuki, T., Takigawa, N., Takata, M., Kiura, K., & Tanimoto, M. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-0681 · Cited by 194
“mutant EGFR compared with the wild-type receptor (20).”
BackgroundOncogenic 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
“These mutations, while activating the kinase, also conferred sensitivity to treatment [52,74].”
BackgroundFatty acid synthase mediates EGFR palmitoylation in EGFR mutated non‐small cell lung cancer
Ali, A., Levantini, E., Teo, J. T., Goggi, J., Clohessy, J. G., Wu, C., Chen, L., Yang, H. H., Krishnan, I., Kocher, O. N., et al. (2018) · EMBO Molecular Medicine · doi:10.15252/emmm.201708313 · Cited by 187
“A rationale for the differences seen in the functional impact of palmitoylation on EGFR is that the mutational status of EGFR may influence the functional role of palmitoylation on EGFR, as structural differences exist between wild-type and mutant EGFRs (Yun et al, 2007; Lowder et al, 2015).”
BackgroundAcetylene Group, Friend or Foe in Medicinal Chemistry
Talele, T. T. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01617 · Cited by 184
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
“Many disrupt interactions that stabilize the inactive conformation, causing hyperactivity and probably oncogene addiction [1,71,73].”
BackgroundMolecular Epidemiology of the Main Druggable Genetic Alterations in Non-Small Cell Lung Cancer
Fois, S. S., Paliogiannis, P., Zinellu, A., Fois, A. G., Cossu, A., & Palmieri, G. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22020612 · Cited by 200
“These mutations destabilize the autoinhibited conformation of th receptor, and the protein is then constitutionally activated to produce its pro-oncogenic effects [18].”
BackgroundEffects of oncogenic mutations on the conformational free-energy landscape of EGFR kinase
Sutto, L., & Gervasio, F. L. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1221953110 · Cited by 181
“Two L858R-selective, ATP-competitive tyrosine kinase inhibitors (TKIs), erlotinib and gefitinib (16, 20), are in clinical use (18).”
BackgroundInfluentialThe 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
“Because activating EGFR-mutant oncogenic variants, including L858R and exon 19 small in-frame deletions, assume constitutively active kinase conformations (19, 20), it is anticipated that HKI-272 will not function as an effective inhibitor against primary activating mutant EGFRs.”
BackgroundResultInfluentialCatalytic Mechanisms and Regulation of Protein Kinases
Wang, Z., & Cole, P. A. (2014) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/b978-0-12-397918-6.00001-x · Cited by 182
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
“The structure was solved by the difference Fourier method using the previously reported EGFR/AMP-PnP structure (PDB ID code 2ITV) (61) with PHENIX software (88) and then was refined using Coot (90) and PHENIX.”
BackgroundMethodSelf-citationZhang, Y., Sheng, J., Kang, S., Fang, W., Yan, Y., Hu, Z., Hong, S., Wu, X., Qin, T., Liang, W., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0107161 · Cited by 175
“Mutant forms of exon 19 deletion and L858R mutation had a reduced affinity for its natural substrate, ATP, but equivalent or increased affinity for reversible EGFR-TKIs, which explained why tumors with these EGFR mutations had higher sensitivity to TKIs [30,31].”
BackgroundRusso, 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
mTOR mediated anti-cancer drug discovery
Liu, Q., Thoreen, C. C., Wang, J., Sabatini, D. M., & Gray, N. S. (2009) · Drug Discovery Today Therapeutic Strategies · doi:10.1016/j.ddstr.2009.12.001 · Cited by 178
“By analogy with other quinoline -derived kinase inhibitors[33], BEZ235 was proposed to form a hydrogen bond with the kinase hinge using the quinoline nitrogen atom [34].”
Nukaga, S., Yasuda, H., Tsuchihara, K., Hamamoto, J., Masuzawa, K., Kawada, I., Naoki, K., Matsumoto, S., Mimaki, S., Ikemura, S., et al. (2017) · Cancer Research · doi:10.1158/0008-5472.can-16-2359 · Cited by 182
“報 告 番 号 氏 名 甲 乙 第 号 （ 内容 の要 旨 ） 主 論 文 題 名 上皮成長因子受容体（epidermal growth factor receptor：EGFR）遺伝子変異陽性肺癌で はEGFRチロシンキナーゼ阻害剤（tyrosine kinase inhibitor：TKI）が高い抗腫瘍効果を示 すが、経過中に耐性化することが問題である。第一、第二世代EGFR-TKIを使用した患者 の半数でEGFR T790M二次変異が生じ、1年程度で効果が見られなくなる。二次変異に有 効な第三世代EGFR-TKIが開発されたが、同様に耐性化することが知られている。第三世 代EGFR-TKIの耐性機序は、チロシンキナーゼ部位の…”
BackgroundThe Development of HKI‐272 and Related Compounds for the Treatment of Cancer
Wissner, A., & Mansour, T. S. (2008) · Archiv der Pharmazie · doi:10.1002/ardp.200800009 · Cited by 179
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
Park, J., Yang, J., Wenzel, A. T., Ramachandran, A., Lee, W. J., Daniels, J., Kim, J., Martínez-Escala, E., Amankulor, N. A., Pro, B., et al. (2017) · Blood · doi:10.1182/blood-2017-02-768234 · Cited by 177
Self-citationMcCubrey, J. A., Steelman, L. S., Kempf, C., Chappell, W. H., Abrams, S. L., Stivala, F., Malaponte, G., Nicoletti, F., Libra, M., Bäsecke, J., et al. (2011) · Journal of Cellular Physiology · doi:10.1002/jcp.22647 · Cited by 177
“…activation of the JOURNAL OF CELLULAR PHYSIOLOGY D R U G R E S I S T A N C E D U E T O M U T A T I O N S I N S I G N A L I N G P A T H W A Y S 2769 EGFR and increased affinity for the drug and decreased affinity for ATP (Carey et al., 2006; Zhang et al., 2006; Yun et al., 2007; Yun et al., 2008).”
BackgroundAcquired resistance to third-generation EGFR-TKIs and emerging next-generation EGFR inhibitors
Du, X., Yang, B., An, Q., Assaraf, Y. G., Cao, X., & Xia, J. (2021) · The Innovation · doi:10.1016/j.xinn.2021.100103 · Cited by 171
Kancha, R. K., von Bubnoff, N., Peschel, C., & Duyster, J. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-1757 · Cited by 168
Metadata
- Authors
- Yun, C.-H., Boggon, T. J., Li, Y., Woo, M. S., Greulich, H., Meyerson, M., & Eck, M. J.
- Affiliations
- Harvard University (US)
- Dana-Farber Cancer Institute (US)
- Broad Institute (US)
- Corresponding author
- Eck, Michael J.
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2007-03
- Volume
- 11
- Issue
- 3
- Pages
- 217-227
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC1939942
- OpenAlex
- W2111109297
- Cited by
- 1,192
- References
- 54
- Citations by year
- 2026: 58 · 2025: 75 · 2024: 78 · 2023: 84 · 2022: 79 · 2021: 59 · 2020: 72 · 2019: 49 · 2018: 58 · 2017: 57 · 2016: 55 · 2015: 79 · 2014: 63 · 2013: 74 · 2012: 51
- FWCI
- 40.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (CA116020, CA080942)
- Leukemia and Lymphoma Society
- 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, non-small cell lung cancer, EGFR mutation, L858R, kinase activation, gefitinib, AEE788, staurosporine, kinase inhibitor binding, crystal structure, catalytic acceleration, inhibitor sensitivity
- MeSH terms
- Gefitinib, Lapatinib, Antineoplastic Agents, Binding Sites, Carcinoma, Non-Small-Cell Lung, Enzyme Activation, Humans, Lung Neoplasms, Models, Molecular, Mutation, Protein Conformation, Purines, Quinazolines, Protein Structure, Tertiary, Crystallography, X-Ray, Staurosporine, ErbB Receptors
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