Epidermal Growth Factor Receptor Mutants from Human Lung Cancers Exhibit Enhanced Catalytic Activity and Increased Sensitivity to Gefitinib
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Abstract
Somatic mutations within the epidermal growth factor receptor (EGFR) kinase domain are detected in 10% to 30% of human non–small cell lung cancers and are correlated with striking clinical responses in a subset of patients treated with EGFR kinase inhibitors, such as gefitinib and erlotinib. Cell-based studies suggest that these mutant EGFRs promote increased autophosphorylating activity on a subset of EGFR COOH-terminal tyrosines and the consequent engagement of a subset of downstream effectors. Because EGFR function is regulated at multiple levels in vivo, and it is therefore difficult to assess the direct consequences of these mutations on EGFR enzyme function, we measured EGFR catalytic activity in in vitro kinase assays using purified recombinant proteins corresponding to the cytoplasmic domain of wild-type and two frequently detected EGFR mutants (DelL747-P753insS and L858R). Both mutants exhibit substantially increased autophosphorylating activity relative to wild-type EGFR, and they exhibit distinct reaction kinetics. In addition, the mutant kinases are more sensitive to kinase inhibition by gefitinib, which seems to reflect their increased drug affinity. These findings suggest that the altered signaling properties and drug sensitivity of these EGFR mutants that have been observed in vivo largely result from differences in the catalytic properties of the kinase. In addition, we find that the T790M secondary “drug resistance mutation” of EGFR, which frequently arises in relapsed patients that initially responded to treatment, confers enhanced kinase activity to primary activating EGFR alleles and may, therefore, be oncogenic in some contexts. [Cancer Res 2007;67(5):2325–30]
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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 [56]
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 [56]
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 [56]
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- Authors
- Mulloy, R., Ferrand, A., Kim, Y., Sordella, R., Bell, D. W., Haber, D. A., Anderson, K. S., & Settleman, J.
- Affiliations
- Harvard University (US)
- 2Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut
- Yale University (US)
- ORCID
- Venue
- Cancer Research
- Published
- 2007-03-01
- Volume
- 67
- Issue
- 5
- Pages
- 2325-2330
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2129787264
- Cited by
- 192
- References
- 21
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 3 · 2023: 4 · 2022: 3 · 2021: 7 · 2020: 4 · 2019: 3 · 2018: 10 · 2017: 11 · 2016: 9 · 2015: 13 · 2014: 16 · 2013: 15 · 2012: 15
- FWCI
- 16.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- V Foundation for Cancer Research
- National Institutes of Health
- National Cancer Institute (R01CA115830)
- National Institute of General Medical Sciences (R01-GM71805)
- 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
- epidermal growth factor receptor, EGFR mutation, non-small cell lung cancer, gefitinib, erlotinib, kinase activity, autophosphorylation, L858R mutation, T790M mutation, drug resistance, kinase inhibitor sensitivity, oncogenicity
- MeSH terms
- Gefitinib, Animals, Antineoplastic Agents, Catalysis, Cells, Cultured, Humans, Lung Neoplasms, Phosphotransferases, Quinazolines, Substrate Specificity, Baculoviridae, Spodoptera, Drug Resistance, Neoplasm, Mutant Proteins, 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.
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