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Published on: April 22, 2019
YAP1 is a potential biomarker for cetuximab resistance in head and neck cancer
Fredrik Jerhammar1, Ann-Charlotte Johansson1, Rebecca Ceder2
1Division of Oto-Rhino-Laryngology and Head and Neck Surgery, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
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®).
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 Spearman's 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.
Insights
YAP1 gene amplification is linked to resistance against cetuximab (Erbitux®) in head and neck squamous cell carcinoma (HNSCC). This finding suggests YAP1 as a potential biomarker for predicting treatment response in HNSCC patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Epidermal growth factor receptor (EGFR) targeted therapy shows variable efficacy in head and neck squamous cell carcinoma (HNSCC).
- Biomarkers are needed to predict treatment response to EGFR-targeting antibodies like cetuximab (Erbitux®).
Purpose of the Study:
- To identify biomarkers predicting treatment response to cetuximab in HNSCC.
- To investigate the role of gene copy number alterations in cetuximab resistance.
Main Methods:
- Assessed intrinsic cetuximab sensitivity of 32 HNSCC cell lines.
- Performed gene copy number analysis using Affymetrix SNP 6.0 platform on resistant and sensitive cell lines.
- Verified findings with quantitative real-time PCR and investigated functional importance using siRNA technology.
Main Results:
- Identified YAP1 gene amplification in cetuximab-resistant HNSCC cell lines.
- YAP1 amplification correlated with higher mRNA levels and conferred cetuximab resistance.
- YAP1 knockdown increased cetuximab sensitivity, and clinical data confirmed YAP1 amplifications in HNSCC.
Conclusions:
- YAP1 amplification is associated with cetuximab resistance in HNSCC.
- YAP1 may serve as a novel predictive biomarker for cetuximab therapy in HNSCC.
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