Structures of Lung Cancer-Derived EGFR Mutants and Inhibitor Complexes: Mechanism of Activation and Insights into Differential Inhibitor Sensitivity
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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 sensitivity of EGFR-L858R and exon 19 deletions to TKIs stems from enhanced intrinsic affinity for TKIs and markedly decreased affinity for ATP.
“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]
The homology model of the inactive state suggests a mechanism of activation related to L858R.
“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]
Beyond the inserted glycine, the polypeptide conformation is similar to WT and L858R kinases.
“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]
EGFR mutations are expected to activate EGFR by destabilizing the inactive form of EGFR without ligand stimulation.
“EGFR mutations are expected to activate the EGFR by destabilizing the inactive form of EGFR without ligand stimulation [7–9].”
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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.
- 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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