Structural and mechanistic underpinnings of the differential drug sensitivity of EGFR mutations in non-small cell lung cancer
Open accessAbstract
EGFR and other ErbB-family tyrosine kinases are overexpressed in many human tumors, and their aberrant expression and mutational activation is associated with the development, progression and aggressiveness of a number of malignancies. Thus the EGFR kinase has long been recognized as a potential drug target in oncology, and small-molecule inhibitors have been under development for more than two decades. As a result of their effectiveness in treating non-small cell lung cancers (NSCLCs) driven by somatic mutations in the EGFR kinase, gefitinib and erlotinib were the first EGFR tyrosine kinase inhibitors (TKIs) approved for clinical use. Ironically, these drugs found their target against mutant forms of the EGFR kinase, which have altered enzyme active sites, and not against the wild type (WT) kinase against which their potency and selectivity was carefully honed. Here we review recent structural and enzymological studies that explore the exquisite sensitivity of a subset of these lung cancer mutants to gefitinib and erlotinib. We discuss available structural evidence for the mechanisms of activation of the EGFR kinase by these mutants, and compare it to physiologic activation of the kinase by ligand-induced dimerization. Finally, we consider the mechanisms by which the secondary T790M "gatekeeper" mutation confers resistance to gefitinib and erlotinib.
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The C-helix contains key active site residue E762 just N-terminal to the insertion site.
“The C-helix contains a key active site residue, E762, just N-terminal to the site of the insertion 50.”
From Structural, Biochemical, and Clinical Characterization of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer (2013) · cites this paper as [50]
The EGFR-T790M mutation confers resistance by reversing the sensitization conferred by primary activating mutations.
“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 [50]
The dose-limiting toxicities of gefitinib and erlotinib arise from inhibition of WT EGFR in normal tissues.
“Because the dose-limiting toxicities of gefitinib and erlotinib arise from inhibition of WT EGFR in normal tissues, the enhanced sensitivity of these mutants relative to WT EGFR effectively creates the “therapeutic window” that makes gefitinib and erlotinib useful drugs 39,50,56.”
From Structural, Biochemical, and Clinical Characterization of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer (2013) · cites this paper as [50]
The enhanced sensitivity of L858R and exon 19 deletion mutants relative to WT EGFR creates the therapeutic window that makes gefitinib and erlotinib useful drugs.
“Because the dose-limiting toxicities of gefitinib and erlotinib arise from inhibition of WT EGFR in normal tissues, the enhanced sensitivity of these mutants relative to WT EGFR effectively creates the “therapeutic window” that makes gefitinib and erlotinib useful drugs 39,50,56.”
From Structural, Biochemical, and Clinical Characterization of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer (2013) · cites this paper as [50]
The similar ATP and TKI binding properties of D770_N771insNPG compared with WT EGFR suggest that it will be difficult to achieve the requisite selectivity versus WT receptor.
“Additionally, the similar ATP and TKI binding properties of this mutant, as compared with WT EGFR, suggest that it will be difficult to achieve the requisite selectivity versus the WT receptor 39,50,56,58,59.”
From Structural, Biochemical, and Clinical Characterization of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer (2013) · cites this paper as [50]
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- Authors
- Eck, M. J., & Yun, C.-H.
- Affiliations
- Harvard University (US)
- Corresponding author
- Eck, Michael J.
- Venue
- Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
- Publisher
- Elsevier BV
- Published
- 2010-03
- Volume
- 1804
- Issue
- 3
- Pages
- 559-566
- ISSN
- 1570-9639 (ISSN-L)
- PMC
- PMC2859716
- OpenAlex
- W2006315580
- Cited by
- 225
- References
- 40
- Citations by year
- 2026: 14 · 2025: 20 · 2024: 11 · 2023: 13 · 2022: 27 · 2021: 16 · 2020: 23 · 2019: 6 · 2018: 22 · 2017: 11 · 2016: 8 · 2015: 14 · 2014: 12 · 2013: 7 · 2012: 10
- FWCI
- 1.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (P01HL048675)
- National Cancer Institute (R01CA116020, R01CA080942)
- 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 mutation, non-small cell lung cancer, gefitinib, erlotinib, tyrosine kinase inhibitors, drug resistance, kinase activation mechanism, ligand-induced dimerization, kinase structure
- MeSH terms
- Erlotinib Hydrochloride, Gefitinib, Animals, Enzyme Activation, Humans, Lung Neoplasms, Mutation, Quinazolines, Structure-Activity Relationship, Protein Structure, Tertiary, Drug Resistance, Neoplasm, Catalytic Domain, Protein Kinase Inhibitors, Small Cell Lung Carcinoma, ErbB Receptors
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