Functional Analysis of Epidermal Growth Factor Receptor (EGFR) Mutations and Potential Implications for EGFR Targeted Therapy

Kancha, Rama Krishna; von Bubnoff, Nikolas; Peschel, Christian; Duyster, Justus

doi:10.1158/1078-0432.ccr-08-1757

Cited by 168Lung Cancer Treatments and MutationsHER2/EGFR in Cancer ResearchCancer Genomics and Diagnostics

Functional Analysis of Epidermal Growth Factor Receptor (EGFR) Mutations and Potential Implications for EGFR Targeted Therapy

Kancha, Rama Krishna, von Bubnoff, Nikolas, Peschel, Christian, Duyster, Justus·2009·Clinical Cancer Research

DOI 10.1158/1078-0432.ccr-08-1757

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Abstract

PURPOSE: Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) might be predictive for clinical response to EGFR inhibitor treatment. However, retrospective analyses of EGFR mutations in clinical trials have shown inconclusive results and the effect of EGFR sequencing in NSCLC is still controversial. Because the vast majority of EGFR mutations described have not been functionally characterized, simple correlation of mutational status and treatment response may not provide reliable information about the predictive value of EGFR mutations. Thus, we aimed to characterize a comprehensive panel of clinically observed EGFR mutations. EXPERIMENTAL DESIGN AND RESULTS: A panel of 30 EGFR mutations was cloned and characterized for kinase activity and the ability to confer growth factor independence. Interestingly, 4 of 30 EGFR mutations showed no kinase activity even after ligand stimulation and were not able to confer growth factor independence. Ba/F3 cells expressing activating EGFR mutants were then used to test the efficacy of EGFR inhibitors in a cell proliferation assay. IC(50) values were calculated for gefitinib, erlotinib, and AEE788. We show that the sensitivity of EGFR mutations toward different inhibitors varies significantly, thus establishing a comprehensive sensitivity profile for each inhibitor. CONCLUSIONS: EGFR mutations identified in NSCLC patients display distinct biological features. The variability in kinase activity, transforming potential, and sensitivity to EGFR inhibitors has to be considered in clinical studies aiming to correlate mutational status and drug response. The identification of comprehensive drug resistance profiles opens the opportunity to test alternative EGFR inhibitors in vitro.

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From Heterogeneous Responses to Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs) in Patients with Uncommon EGFR Mutations: New Insights and Future Perspectives in this Complex Clinical Scenario (2019) · cites this paper as [34]
Preclinical studies show lower efficacy of 1G EGFR-TKIs for uncommon EGFR mutations.
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From Sensitivities to various epidermal growth factor receptor‐tyrosine kinase inhibitors of uncommon epidermal growth factor receptor mutations L861Q and S768I: What is the optimal epidermal growth factor receptor‐tyrosine kinase inhibitor? (2016) · cites this paper as [41]

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Authors: Kancha, R. K., von Bubnoff, N., Peschel, C., & Duyster, J.
Affiliations: Technical University of Munich (DE)
Authors' Affiliation: Department of Internal Medicine III, Technical University of Munich, Munich, Germany
ORCID: Kancha, Rama Krishna
Peschel, Christian
Duyster, Justus
Venue: Clinical Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2009-01-15
Volume: 15
Issue: 2
Pages: 460-467
ISSN: 1078-0432 (ISSN-L)
1557-3265
DOI: 10.1158/1078-0432.ccr-08-1757
OpenAlex: W2150213614
Cited by: 168
References: 35
Citations by year: 2026: 4 · 2025: 7 · 2024: 4 · 2023: 6 · 2022: 11 · 2021: 8 · 2020: 11 · 2019: 9 · 2018: 13 · 2017: 13 · 2016: 12 · 2015: 14 · 2014: 13 · 2013: 11 · 2012: 7
FWCI: 8.98
Type: journal article
Language: en
Open access: closed
Locations: Clinical Cancer Research (publishedVersion)
PubMed (publishedVersion)
mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
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, non-small cell lung cancer, EGFR inhibitors, gefitinib, erlotinib, AEE788, kinase activity, growth factor independence, drug sensitivity, predictive biomarkers, drug resistance, Ba/F3 cells
MeSH terms: Amino Acid Sequence, Animals, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Cell Membrane, Humans, Lung Neoplasms, Medical Oncology, Molecular Sequence Data, Mutation, Inhibitory Concentration 50, NIH 3T3 Cells, Cell Line, Tumor, Mice, ErbB Receptors

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Functional Analysis of Epidermal Growth Factor Receptor (EGFR) Mutations and Potential Implications for EGFR Targeted Therapy

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