An Alternative Inhibitor Overcomes Resistance Caused by a Mutation of the Epidermal Growth Factor Receptor
Open accessAbstract
Mutations of the epidermal growth factor receptor (EGFR) gene have been identified in non–small cell lung cancer specimens from patients responding to anilinoquinazoline EGFR inhibitors. However, clinical resistance to EGFR inhibitor therapy is commonly observed. Previously, we showed that such resistance can be caused by a second mutation of the EGFR gene, leading to a T790M amino acid change in the EGFR tyrosine kinase domain and also found that CL-387,785, a specific and irreversible anilinoquinazoline EGFR inhibitor, was able to overcome this resistance on the biochemical level. Here, we present the successful establishment of a stable Ba/F3 cell line model system for the study of oncogenic EGFR signaling and the functional consequences of the EGFR T790M resistance mutation. We show the ability of gefitinib to induce growth arrest and apoptosis in cells transfected with wild-type or L858R EGFR, whereas the T790M mutation leads to high-level functional resistance against gefitinib and erlotinib. In addition, CL-387,785 is able to overcome resistance caused by the T790M mutation on a functional level, correlating with effective inhibition of downstream signaling pathways. Similar data was also obtained with the use of the gefitinib-resistant H1975 lung cancer cell line. The systems established by us should prove useful for the large-scale screening of alternative EGFR inhibitor compounds against the T790M or other EGFR mutations. These data also support the notion that clinical investigations of compounds similar to CL-387,785 may be useful as a treatment strategy for patients with resistance to EGFR inhibitor therapy caused by the T790M mutation.
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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 [202]
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- Authors
- Kobayashi, S., Ji, H., Yuza, Y., Meyerson, M., Wong, K.-K., Tenen, D. G., & Halmos, B.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Dana-Farber Cancer Institute (US)
- 1Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School;
- Venue
- Cancer Research
- Published
- 2005-08-15
- Volume
- 65
- Issue
- 16
- Pages
- 7096-7101
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2062766483
- Cited by
- 272
- References
- 21
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 4 · 2023: 16 · 2022: 3 · 2021: 1 · 2020: 11 · 2019: 6 · 2018: 10 · 2017: 11 · 2016: 12 · 2015: 4 · 2014: 16 · 2013: 12 · 2012: 16
- FWCI
- 22.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (P20CA090578, P20-CA090578-01A1)
- 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
- epidermal growth factor receptor, T790M mutation, EGFR inhibitor resistance, gefitinib, erlotinib, non-small cell lung cancer, H1975 cell line, downstream signaling pathways, apoptosis, growth arrest, drug resistance testing
- MeSH terms
- Gefitinib, Animals, Antineoplastic Agents, DNA-Binding Proteins, Drug Interactions, Interleukin-3, Milk Proteins, Mutation, Phosphorylation, Proto-Oncogene Proteins, Quinazolines, Trans-Activators, Apoptosis, Protein Serine-Threonine Kinases, Genes, erbB-1, Cell Line, Tumor, Protein Kinase Inhibitors, Cell Growth Processes, STAT5 Transcription Factor, Proto-Oncogene Proteins c-akt, Mice, ErbB Receptors
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