Cited by 1,192Lung Cancer Treatments and MutationsHER2/EGFR in Cancer ResearchProtein Kinase Regulation and GTPase Signaling

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Structures of Lung Cancer-Derived EGFR Mutants and Inhibitor Complexes: Mechanism of Activation and Insights into Differential Inhibitor Sensitivity

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Yun, Cai-Hong, Boggon, Titus J., Li, Yiqun, Woo, Michele S., Greulich, Heidi, Meyerson, Matthew, Eck, Michael J.·2007·Cancer Cell

DOI 10.1016/j.ccr.2006.12.017PMC PMC1939942

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Abstract

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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Background
Monomer Preference of EGFR Tyrosine Kinase Inhibitors Influences the Synergistic Efficacy of Combination Therapy with Cetuximab
Oashi, A., Yasuda, H., Kobayashi, K., Tani, T., Hamamoto, J., Masuzawa, K., Manabe, T., Terai, H., Ikemura, S., Kawada, I., et al. (2019) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-18-1036 · Cited by 4
“Mutated forms of EGFR, such as those with deletions around the LREA motif, encoded by exon 19, or the point mutation L858R, encoded by exon 21, demonstrate increased affinity for EGFR-TKIs and decreased affinity for ATP compared with wild-type EGFR, which creates a therapeutic window for these ATP-competitive EGFR-TKI…”
Background
How good are comparative models in the understanding of protein dynamics?
Yazhini, A., & Srinivasan, N. (2020) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.25879 · Cited by 5
“Information on ATP-binding sites and asymmetric dimer interfaces was obtained from previous studies.(50,51)”
Method
Mutation patterns of epidermal growth factor receptor gene in non-small cell lung cancer among Egyptian patients
El-Metnawy, W., Qenawi, M., Sabet, S., & Bassiony, H. (2022) · Egyptian Journal of Basic and Applied Sciences · doi:10.1080/2314808x.2021.2022924 · Cited by 5
“related to responses to TKIs but with less sensitivity than the common mutations (19, 21) in vitro [53,61,62].”
Background
Discovery of a Highly Potent and Broadly Effective Epidermal Growth Factor Receptor and HER2 Exon 20 Insertion Mutant Inhibitor
Jang, J., Son, J., Park, E., Kosaka, T., Saxon, J. A., Clercq, D. J. H. D., Choi, H. G., Tanizaki, J., Eck, M. J., Janne, P. A., et al. (2018) · Angewandte Chemie · doi:10.1002/ange.201805187 · Cited by 5
Self-citation
Gefitinib, but Not Erlotinib, is a Possible Inducer of Fra-1-mediated Interstitial Lung Disease
Takada, Y., & Matsuo, K. (2012) · The Keio Journal of Medicine · doi:10.2302/kjm.2011-0009-oa · Cited by 5
Molekulardiagnostik des Lungenkarzinoms zur Therapiestratifizierung
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Application of Free–Wilson Selectivity Analysis for Combinatorial Library Design
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Molecular Crosstalk and Therapeutic Synergy: Tyrosine Kinase Inhibitors and Cannabidiol in Oral Cancer Treatment
AlRaheem, Z. S. G., Le, T. T., Seyfoddin, A., & Li, Y. (2025) · Current Issues in Molecular Biology · doi:10.3390/cimb47080584 · Cited by 4
“In exon 21, the L858R point mutation, which substitutes leucine 858 with arginine, is the most prevalent EGFR mutation in lung cancer, accounting for around 40% of all cases, but it is rarely seen in HNSCC [75,76].”
Self-citation
A molecular dynamics protocol for rapid prediction of EGFR overactivation and its application to the rare mutations S768I, S768N, D761N
Behn, J., Deepak, R. N. V. K., Hu, J., & Fan, H. (2025) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2025.07.046 · Cited by 5
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Allele-Specific CRISPR-Cas9-Based Ratiometric Fluorescence Platform for Portable EGFR L858R Mutation Detection
Ming, W., Zhu, Y., Li, L., Wang, T., Pan, A., Xu, Q., Ji, H., Qin, Y., & Wu, L. J. (2025) · Analytical Chemistry · doi:10.1021/acs.analchem.5c05548 · Cited by 4
ErbB family receptor dimerization dynamics and dysregulation via long-term single-molecule imaging
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Self-citation
Advances in the Treatment of Rare Epidermal Growth Factor Receptor Mutations in Advanced Nonsmall-Cell Lung Cancer
Yu, L., Wang, R., Zhao, Y., Wu, Y., Wang, L., Chen, H., He, Z., Wang, Q., & Wu, Y. (2023) · Technology in Cancer Research & Treatment · doi:10.1177/15330338231168466 · Cited by 4
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From Lab to Target: Pyrazole, Pyrazoline and Fused Pyrazole Derivatives as Receptor Tyrosine Kinase Inhibitors in Cancer Therapy
Sawiris, M. M., Khalil, O. M., Halim, P. A., & Hassan, M. S. A. (2025) · Archiv der Pharmazie · doi:10.1002/ardp.70061 · Cited by 5
Identification of a new insertion in exon 20 of EGFR in a woman with NSCLC
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“Two EGFR X-ray crystal complex structures were collected from the RCSB protein database (PDB), namely 2J6M (Yun et al., 2007) and 4G5J (Solca et al., 2012).”
Method
Leucine Zipper Downregulated in Cancer-1 Interacts with Clathrin Adaptors to Control Epidermal Growth Factor Receptor (EGFR) Internalization and Gefitinib Response in EGFR-Mutated Non-Small Cell Lung Cancer
Huang, H., Hung, P.-F., Chen, Y.-P., & Lee, C. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25031374 · Cited by 3
“EGFR M exhibits greater affinity for gefitinib and erlotinib than does the wild-type version [6,9], making patients harboring EGFR M more responsive to EGFR-TKI therapy.”
Background
IMesCuCl/TBHP system for aqueous oxidative amidation: Synthesis of new amide derivatives as EGFR targeting anti-breast cancer agents and computational studies
Sagam, R. R., Azam, M., Al-Resayes, S. I., Banothu, D., Nukala, S. K., & Thirukovela, N. S. (2024) · Journal of Molecular Structure · doi:10.1016/j.molstruc.2024.137922 · Cited by 4
An agent-based modelling framework to study growth mechanisms in EGFR-L858R mutant cell alveolar type II cells
Coggan, H., Weeden, C. E., Pearce, P., Dalwadi, M. P., Magness, A. J., Swanton, C., & Page, K. M. (2024) · Royal Society Open Science · doi:10.1098/rsos.240413 · Cited by 4
“Biochemical and structural studies have shown that the EGFR-L858R mutation promotes dimerization [20] and destabilizes the inactive formation [21] of EGFR, and thus causes abnormal levels of receptor activity.”
Background
Prolonged survival with erlotinib followed by afatinib in a caucasian smoker with metastatic, poorly differentiated large cell carcinoma of the lung: a case report
González, M. Á. S. (2015) · Cancer Biology & Therapy · doi:10.1080/15384047.2015.1070993 · Cited by 4
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Kang, S. K., Lee, S. W., Woo, D., Sim, J., & Suh, Y. (2017) · Synthetic Communications · doi:10.1080/00397911.2017.1359627 · Cited by 4
Synthesis, Characterization, and Preliminary In Vitro Cytotoxic Evaluation of a Series of 2-Substituted Benzo [d] [1,3] Azoles
Linares-Anaya, O., Avila‐Sorrosa, A., Díaz-Cedillo, F., Gil-Ruiz, L. Á., Correa‐Basurto, J., Salazar‐Mendoza, D., Orjuela, A. L., Alí‐Torres, J., Ramírez‐Apán, M. T., & Morales‐Morales, D. (2021) · Molecules · doi:10.3390/molecules26092780 · Cited by 4
“These tridimensional structures were taken from PDB codes 3ERT [59], 4OAR [60], 2J6M [61], and 4DRH [62].”
Method
Correlation of PD-L1 Expression with Clinicopathological and Genomic Features in Chinese Non-Small-Cell Lung Cancer
Li, Y., Li, C., Jiang, Y., Han, X., Liu, S., Xu, X., Tang, W., Ou, Q., Bao, H., Wu, X., et al. (2022) · Journal of Oncology · doi:10.1155/2022/1763778 · Cited by 5
Self-citation
Review on EGFR-ERK1/2 signaling cascade: implications on cell proliferation in health and disease
Fetoh, M. E. A., Abdel‐Fattah, M. M., Afify, H., Ramadan, L. A. A., & Mohamed, W. R. (2023) · Egyptian Pharmaceutical Journal · doi:10.4103/epj.epj_52_23 · Cited by 4
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Yang, J., Tu, Z., Xu, X., Luo, J., Xing, Y. T., Ran, C., Mao, X., Ding, K., & Qiao, C. (2017) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2017.02.023 · Cited by 4
Molecular Diagnosis and Targeting for Lung Cancer
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Label-free real-time ultrasensitive monitoring of non-small cell lung cancer cell interaction with drugs
Dai, H., Jiao, Y., Sun, Z., Cao, Z., & Chen, X. (2018) · Biomedical Optics Express · doi:10.1364/boe.9.004149 · Cited by 4
Lung Cancer Metastasis
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Structural Features of the Kinase Domain
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Computational delineation of tyrosyl-substrate recognition and catalytic landscapes by the epidermal growth factor receptor tyrosine kinase domain
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“The recent availability of several crystal structures of the EGFR kinase domain [7-10] have brought to focus the importance of molecular details in the structure-function relationship, including the mechanisms for substrate recognition and phosphoryl transfer.”
Background
Impact of epidermal growth factor receptor gene expression level on clinical outcomes in epidermal growth factor receptor mutant lung adenocarcinoma patients taking first-line epidermal growth factor receptor–tyrosine kinase inhibitors
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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.
ORCID: Yun, Cai-Hong
Boggon, Titus J.
Li, Yiqun
Greulich, Heidi
Meyerson, Matthew
Eck, Michael J.
Venue: Cancer Cell
Publisher: Elsevier BV
Published: 2007-03
Volume: 11
Issue: 3
Pages: 217-227
ISSN: 1535-6108 (ISSN-L)
DOI: 10.1016/j.ccr.2006.12.017
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: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 2366 d)
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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Structures of Lung Cancer-Derived EGFR Mutants and Inhibitor Complexes: Mechanism of Activation and Insights into Differential Inhibitor Sensitivity

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