Oncogenic Transformation by Inhibitor-Sensitive and -Resistant EGFR Mutants

Greulich, Heidi; Chen, Tzu-Hsiu; Feng, Whei; Jänne, Pasi A; Alvarez, James V; Zappaterra, Mauro; Bulmer, Sara E; Frank, David A; Hahn, William C; Sellers, William R; Meyerson, Matthew

doi:10.1371/journal.pmed.0020313

Cited by 679Lung Cancer Treatments and MutationsHER2/EGFR in Cancer ResearchCancer Genomics and Diagnostics

Oncogenic Transformation by Inhibitor-Sensitive and -Resistant EGFR Mutants

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Greulich, Heidi, Chen, Tzu-Hsiu, Feng, Whei, Jänne, Pasi A, Alvarez, James V, Zappaterra, Mauro, Bulmer, Sara E, Frank, David A +3 more·2005·PLoS Medicine

DOI 10.1371/journal.pmed.0020313PMC PMC1240052

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Abstract

BACKGROUND: Somatic mutations in the kinase domain of the epidermal growth factor receptor tyrosine kinase gene EGFR are common in lung adenocarcinoma. The presence of mutations correlates with tumor sensitivity to the EGFR inhibitors erlotinib and gefitinib, but the transforming potential of specific mutations and their relationship to drug sensitivity have not been described. METHODS AND FINDINGS: Here, we demonstrate that EGFR active site mutants are oncogenic. Mutant EGFR can transform both fibroblasts and lung epithelial cells in the absence of exogenous epidermal growth factor, as evidenced by anchorage-independent growth, focus formation, and tumor formation in immunocompromised mice. Transformation is associated with constitutive autophosphorylation of EGFR, Shc phosphorylation, and STAT pathway activation. Whereas transformation by most EGFR mutants confers on cells sensitivity to erlotinib and gefitinib, transformation by an exon 20 insertion makes cells resistant to these inhibitors but more sensitive to the irreversible inhibitor CL-387,785. CONCLUSION: Oncogenic transformation of cells by different EGFR mutants causes differential sensitivity to gefitinib and erlotinib. Treatment of lung cancers harboring EGFR exon 20 insertions may therefore require the development of alternative kinase inhibition strategies.

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CL-387785 has shown potential to overcome T790M mutation-related resistance at functional level.
“CL-387785 has also shown potential to overcome T790M mutation-related resistance at the functional level, possibly by effectively inhibiting downstream signaling pathways.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [201]
These mutant kinases present reduced affinity for ATP, accounting for increased sensitivity to EGFR TKIs compared with wild type, since these inhibitors compete with ATP for binding to the catalytic site.
“These mutant kinases present a reduced affinity for the ATP, accounting for the increased sensitivity to EGFR TKIs compared with the wild type counterparts, since these inhibitors compete with ATP for binding to the catalytic site [10–12].”
From A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): Old successes and future perspectives (2015) · cites this paper as [10]
Most EGFR exon 20 insertion mutations are 1st generation EGFR-TKI resistant mutations.
“Most EGFR exon 20 insertion mutations are 1st generation EGFR-TKIs resistant mutations [15, 18, 19].”
From In vitro modeling to determine mutation specificity of EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants in non-small-cell lung cancer (2015) · cites this paper as [19]
Cell culture and transgenic mouse model studies have shown that mutant EGFR has transforming activity.
“Cell culture and transgenic mouse model studies have shown that mutant EGFR has transforming activity (Greulich et al., 2005; Ji et al., 2006; Politi et al., 2006).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Greulich et al., 2005

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Authors: Greulich, H., Chen, T.-H., Feng, W., Jänne, P. A., Alvarez, J. V., Zappaterra, M., Bulmer, S. E., Frank, D. A., Hahn, W. C., Sellers, W. R., & Meyerson, M.
Affiliations: Broad Institute (US)
Brigham and Women's Hospital (US)
Dana-Farber Cancer Institute (US)
Corresponding author: Greulich, Heidi
Sellers, William R
Meyerson, Matthew
ORCID: Greulich, Heidi
Alvarez, James V
Frank, David A
Hahn, William C
Sellers, William R
Meyerson, Matthew
Venue: PLoS Medicine
Publisher: Public Library of Science (PLoS)
Published: 2005-10-04
Volume: 2
Issue: 11
Pages: e313
ISSN: 1549-1277 (ISSN-L)
1549-1676
DOI: 10.1371/journal.pmed.0020313
PMC: PMC1240052
OpenAlex: W2037873277
Cited by: 677
References: 35
Citations by year: 2026: 9 · 2025: 10 · 2024: 10 · 2023: 22 · 2022: 23 · 2021: 23 · 2020: 16 · 2019: 29 · 2018: 20 · 2017: 27 · 2016: 26 · 2015: 47 · 2014: 27 · 2013: 54 · 2012: 46
FWCI: 45.72
Type: journal article
Language: en
Update notices: correction (2024-09-16)
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (unspecified)
Locations: PLoS Medicine (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: American Cancer Society
Doris Duke Charitable Foundation
Flight Attendant Medical Research Institute
Barr Foundation
National Institutes of Health
National Cancer Institute
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 › Cancer Research › Cancer Genomics and Diagnostics
Keywords: EGFR mutation, oncogenic transformation, lung adenocarcinoma, erlotinib, gefitinib, EGFR inhibitors, exon 20 insertion, autophosphorylation, Shc phosphorylation, STAT pathway, drug resistance, kinase inhibitors
MeSH terms: Erlotinib Hydrochloride, Src Homology 2 Domain-Containing, Transforming Protein 1, Gefitinib, Animals, Antineoplastic Agents, Cell Transformation, Neoplastic, Exons, Humans, Mice, Nude, Mutation, Neoplasms, Experimental, Quinazolines, Transfection, Tumor Stem Cell Assay, Genetic Therapy, Drug Resistance, Neoplasm, NIH 3T3 Cells, Protein Kinase Inhibitors, Adaptor Proteins, Signal Transducing, STAT3 Transcription Factor, Proto-Oncogene Proteins c-akt, Mice, Shc Signaling Adaptor Proteins, ErbB Receptors

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Oncogenic Transformation by Inhibitor-Sensitive and -Resistant EGFR Mutants

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