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YAP1 is a potential biomarker for cetuximab resistance in head and neck cancer
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Not Found:Linkoping Univ, Fac Hlth Sci, Dept Clin and Expt Med, Div Otorhinolaryngol and Head and Neck Surg, Linkoping, Sweden .
Karolinska Institute, Sweden .
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
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2014 (English)In: Oral Oncology, ISSN 1368-8375, E-ISSN 1879-0593, Vol. 50, no 9, 832-839 p.Article in journal (Refereed) Published
Abstract [en]

Objectives: Targeted therapy against the epidermal growth factor receptor (EGFR) only variably represents a therapeutic advance in head and neck squamous cell carcinoma (HNSCC). This study addresses the need of biomarkers of treatment response to the EGFR-targeting antibody cetuximab (Erbitux (R)). Materials and Methods: The intrinsic cetuximab sensitivity of HNSCC cell lines was assessed by a crystal violet assay. Gene copy number analysis of five resistant and five sensitive cell lines was performed using the Affymetrix SNP 6.0 platform. Quantitative real-time PCR was used for verification of selected copy number alterations and assessment of mRNA expression. The functional importance of the findings on the gene and mRNA level was investigated employing siRNA technology. The data was statistically evaluated using Mann-Whitney U-test and Spearmans correlation test. Results: Analysis of the intrinsic cetuximab sensitivity of 32 HNSCC cell lines characterized five and nine lines as cetuximab sensitive or resistant, respectively. Gene copy number analysis of five resistant versus five sensitive cell lines identified 39 amplified protein-coding genes, including YAP1, in the genomic regions 11q22.1 or 5p13-15. Assessment using qPCR verified that YAP1 amplification associated with cetuximab resistance. Amplification of YAP1 correlated to higher mRNA levels, and RNA knockdown resulted in increased cetuximab sensitivity. Assessment of several independent clinical data sets in the public domain confirmed YAP1 amplifications in multiple tumor types including HNSCC, along with highly differential expression in a subset of HNSCC patients. Conclusion: Taken together, we provide evidence that YAP1 could represent a novel biomarker gene of cetuximab resistance in HNSCC cell lines.

Place, publisher, year, edition, pages
Elsevier , 2014. Vol. 50, no 9, 832-839 p.
Keyword [en]
Head and neck cancer; SCCHN; YAP1; Predictive marker; Treatment response; Gene copy number; Drug resistance
National Category
Clinical Medicine
Identifiers
URN: urn:nbn:se:liu:diva-110268DOI: 10.1016/j.oraloncology.2014.06.003ISI: 000340267300011PubMedID: 24993889OAI: oai:DiVA.org:liu-110268DiVA: diva2:744056
Note

Funding Agencies|Swedish Cancer Society [2008/552, 2010/545]; Ake Wiberg foundation; National board of health and welfare; Ostergotland county council; Foundation of Olle Engkvist; Swedish Cancer and Allergy Fund; Swedish Research Council; Swedish Fund for Research

Available from: 2014-09-05 Created: 2014-09-05 Last updated: 2017-12-05

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Jerhammar, FredrikJohansson, Ann-CharlotteWelander, JennyJansson, AgnetaSöderkvist, PeterRoberg, Karin

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Jerhammar, FredrikJohansson, Ann-CharlotteWelander, JennyJansson, AgnetaSöderkvist, PeterRoberg, Karin
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Division of NeuroscienceFaculty of Health SciencesDivision of Cell BiologyDivision of Clinical SciencesDepartment of Clinical Pathology and Clinical GeneticsDepartment of Otorhinolaryngology in Linköping
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