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Journal of Cancer Research and Clinical Oncology

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01.05.2012 | Original Paper

Relevance of MET activation and genetic alterations of KRAS and E-cadherin for cetuximab sensitivity of gastric cancer cell lines

verfasst von: Stefan Heindl, Evelyn Eggenstein, Simone Keller, Julia Kneissl, Gisela Keller, Kathrin Mutze, Sandra Rauser, Georg Gasteiger, Ingo Drexler, Alexander Hapfelmeier, Heinz Höfler, Birgit Luber

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 5/2012

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Abstract

Purpose

The therapeutic activity of the epidermal growth factor receptor (EGFR)-directed monoclonal antibody cetuximab in gastric cancer is currently being investigated. Reliable biomarkers for the identification of patients who are likely to benefit from the treatment are not available. The aim of the study was to examine the drug sensitivity of five gastric cancer cell lines towards cetuximab as a single agent and to establish predictive markers for chemosensitivity in this cell culture model. The effect of a combination of cetuximab with chemotherapy was compared between a sensitive and a nonsensitive cell line.

Methods

EGFR expression, activation and localisation, the presence and subcellular localisation of the cell adhesion molecule E-cadherin as well as MET activation were examined by Western blot analysis, flow cytometry and immunofluorescence staining. Cells were treated with varying concentrations of cetuximab and cisplatin and 5-fluorouracil in tumour-relevant concentrations. The biological endpoint was cell viability, which was measured by XTT cell proliferation assay. Response to treatment was evaluated using statistical methods.

Results

We assessed the activity of cetuximab in five gastric cancer cell lines (AGS, KATOIII, MKN1, MKN28 and MKN45). The viability of two cell lines, MKN1 and MKN28, was significantly reduced by cetuximab treatment. High EGFR expression and low levels of receptor activation were associated with cetuximab responsiveness. MET activation as well as mutations of KRAS and CDH1 (gene encoding E-cadherin) was associated with cetuximab resistance.

Conclusion

These data indicate that our examinations may be clinically relevant, and the candidate markers should therefore be tested in clinical studies.

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Titel: Relevance of MET activation and genetic alterations of KRAS and E-cadherin for cetuximab sensitivity of gastric cancer cell lines
verfasst von: Stefan Heindl
Evelyn Eggenstein
Simone Keller
Julia Kneissl
Gisela Keller
Kathrin Mutze
Sandra Rauser
Georg Gasteiger
Ingo Drexler
Alexander Hapfelmeier
Heinz Höfler
Birgit Luber
Publikationsdatum: 01.05.2012
Verlag: Springer-Verlag
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 5/2012
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-011-1128-4

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Relevance of MET activation and genetic alterations of KRAS and E-cadherin for cetuximab sensitivity of gastric cancer cell lines

Abstract

Purpose

Methods

Results

Conclusion

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Abstract

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Methods

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Conclusion

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