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Published on: August 11, 2017
Relationship of EGFR mutations, expression, amplification, and polymorphisms to epidermal growth factor receptor
Wanqing Liu1, Xiaolin Wu, Wei Zhang
1Department of Medicine, The University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637, USA.
Purpose:
The mechanism of sensitivity and resistance to epidermal growth factor receptor (EGFR) inhibitors is incompletely understood, particularly in cancers other than non-small-cell lung cancer (NSCLC). To understand the variable response to this class of drugs, we used the NCI60 cancer cell lines. We aimed to determine if there are interactions between EGFR expression, mutations, polymorphisms, and gene amplification, and whether these factors are associated with variability in response to EGFR inhibitors.
Experimental Design:
The EGFRVIII and tyrosine kinase (TK) domain mutations were examined in the NCI60 cancer cell lines. Five polymorphisms, -216G/T, -191C/A, intron 1 (CA)n, R497K, and 2607A/G, were genotyped. EGFR amplification was also assessed with high-density single-nucleotide polymorphism chip and real-time PCR, respectively. The results were correlated with cytotoxicity data for erlotinib and other 11 EGFR inhibitors, as well as other publicly available data for these lines.
Results:
All 12 inhibitors behaved similarly. No EGFRVIII but putative TK mutations in two cell lines were found. Both mutant cell lines were insensitive to all inhibitors. Meanwhile, response did not correlate with EGFR amplification but with EGFR gene expression, especially in the cell lines with relatively normal gene status. In addition, EGFR expression was associated with the -216G/T polymorphism but not with the intron 1 (CA)n polymorphism. A combination of -216G/T and R497K polymorphisms was weakly associated with drug response.
Conclusions:
These observations suggest that in addition to TK mutations, germ-line variability may also contribute to the pharmacodynamics of EGFR inhibitors, particularly when EGFR is genetically normal.
Insights
Epidermal growth factor receptor (EGFR) inhibitor response varies due to gene expression and polymorphisms, not just mutations. Germ-line variations influence drug effectiveness, especially in genetically normal EGFR cancers.
Area of Science:
- Oncology
- Pharmacogenomics
- Molecular Biology
Background:
- Sensitivity and resistance mechanisms to epidermal growth factor receptor (EGFR) inhibitors are not fully understood, particularly in cancers beyond non-small-cell lung cancer (NSCLC).
- Understanding variable responses to EGFR inhibitors is crucial for optimizing cancer therapy.
Purpose of the Study:
- To investigate the interplay between EGFR expression, mutations, polymorphisms, and gene amplification in the NCI60 cancer cell lines.
- To determine the association of these genetic factors with variable responses to EGFR inhibitors.
Main Methods:
- Examined EGFRVIII and tyrosine kinase (TK) domain mutations in NCI60 cell lines.
- Genotyped five EGFR polymorphisms: -216G/T, -191C/A, intron 1 (CA)n, R497K, and 2607A/G.
- Assessed EGFR amplification and correlated findings with cytotoxicity data for 12 EGFR inhibitors.
Main Results:
- No EGFRVIII mutations were found; two cell lines had putative TK mutations, rendering them insensitive to all tested inhibitors.
- EGFR response correlated with gene expression, particularly in cell lines with normal gene status, but not EGFR amplification.
- EGFR expression linked to the -216G/T polymorphism; a combination of -216G/T and R497K polymorphisms showed weak association with drug response.
Conclusions:
- Tyrosine kinase (TK) mutations are a key factor in EGFR inhibitor resistance.
- Germ-line genetic variability, in addition to TK mutations, may influence EGFR inhibitor pharmacodynamics.
- These findings are particularly relevant for understanding drug response in cancers with genetically normal EGFR.
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