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Judith Loeffler-Ragg1, Sergej Skvortsov, Bettina Sarg
1Department of Internal Medicine, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria.
Abstract:
Biomarkers that predict response to therapy with inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase remain largely uncharacterized. In order to define proteins involved in potential resistance mechanisms, we examined the effect of gefitinib (ZD1839, Iressa) in the EGFR-positive colon cancer cell lines Caco-2, DiFi, HRT-18 and HT-29. None of them exhibited an activating mutation in exons 19 or 21 of EGFR. Proteome profiling with two-dimensional polyacrylamide gel electrophoresis followed by mass spectrometry revealed 12 proteins differentially expressed in responsive and non-responsive cells. These proteins are involved in metabolic pathways, partially relevant in malignant growth and four of them are known to interact with the EGFR signalling pathway. Ubiquitin carboxyl-terminated hydrolase isozyme L1 (UCH-L1) and galectin-3 are overexpressed in the responsive cell line Caco-2, whereas fatty acid-binding protein (E-FABP) and heat shock protein (hsp) 27 are expressed more in the resistant cell lines HRT-18 and HT-29 suggesting a role in non-responsiveness of cells to gefitinib.
Insights
Identifying biomarkers for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor therapy is crucial. This study found specific proteins like UCH-L1 and galectin-3 in responsive cells, and E-FABP and hsp27 in resistant cells, suggesting their role in gefitinib resistance.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Biomarkers predicting response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are not well-defined.
- Understanding resistance mechanisms is key for effective cancer therapy.
Purpose of the Study:
- To identify proteins involved in gefitinib resistance in EGFR-positive colon cancer cell lines.
- To explore potential biomarkers for predicting response to EGFR tyrosine kinase inhibitor therapy.
Main Methods:
- Utilized gefitinib treatment on four EGFR-positive colon cancer cell lines (Caco-2, DiFi, HRT-18, HT-29).
- Performed proteome profiling using two-dimensional polyacrylamide gel electrophoresis and mass spectrometry.
- Analyzed differential protein expression between responsive and non-responsive cell lines.
Main Results:
- Identified 12 differentially expressed proteins between responsive and non-responsive cells.
- Found ubiquitin carboxyl-terminated hydrolase isozyme L1 (UCH-L1) and galectin-3 overexpressed in the responsive Caco-2 cell line.
- Observed increased expression of fatty acid-binding protein (E-FABP) and heat shock protein (hsp) 27 in resistant cell lines (HRT-18, HT-29).
- Four identified proteins are known to interact with the EGFR signaling pathway.
Conclusions:
- UCH-L1, galectin-3, E-FABP, and hsp27 may play roles in colon cancer cell response or resistance to gefitinib.
- These proteins represent potential biomarkers for predicting therapeutic outcomes with EGFR inhibitors.
- Further research is warranted to elucidate the precise mechanisms of these proteins in EGFR inhibitor resistance.
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