liu.seSearch for publications in DiVA
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
YAP1 Gene Amplification is a Marker for Cetuximab Resistance in Head and Neck Cancer
Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Show others and affiliations
(English)Manuscript (preprint) (Other academic)
Abstract [en]

The epidermal growth factor receptor (EGFR) is commonly overexpressed in head and neck squamous cell carcinomas (HNSCC). The monoclonal antibody cetuximab (Erbitux®) inhibits its signaling and has been approved for treatment of HNSCC. However, since many patients do not benefit from cetuximab treatment, predictive biomarkers of cetuximab response are required. The present study aims at finding novel markers of cetuximab resistance.

The intrinsic cetuximab sensitivity of 35 HNSCC cell lines was determined, and revealed a great variation in the response between cell lines. Five cell lines (14%) were cetuximab sensitive, and 12 (34%) were resistant. Interestingly, two cell lines proliferated after cetuximab treatment.

10 cell lines (five cetuximab sensitive and five cetuximab resistant) were selected for gene copy number array analysis on the Affymetrix SNP 6.0 platform. 39 protein coding genes were amplified in cetuximab resistant cells and normal in sensitive cells, all present on genomic regions 11q22.1 or 5p13-15. Five genes were selected for quantitative PCR  verification, namely, YAP1 and TRPC6 (11q22.1) and PDCD6, TPPP, and PTGER4 (5p13-15). An extended panel of totally 10 cetuximab resistant and 10 sensitive cell lines verified that YAP1 amplified cells are cetuximab resistant.

YAP1 gene amplification was highly correlated to the YAP1 mRNA expression, which was significantly higher in cetuximab resistant cells than in sensitive. YAP1 downregulation resulted in increased cetuximab sensitivity in one of two cetuximab resistant cell lines investigated and growth inhibition in another. We conclude that YAP1 is a marker for cetuximab resistance in head and neck cancer.

National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-76151OAI: oai:DiVA.org:liu-76151DiVA: diva2:512754
Available from: 2012-03-29 Created: 2012-03-29 Last updated: 2012-03-29Bibliographically approved
In thesis
1. Predictive Markers of Treatment Resistance in Head and Neck Squamous Cell Carcinoma
Open this publication in new window or tab >>Predictive Markers of Treatment Resistance in Head and Neck Squamous Cell Carcinoma
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Head and neck cancer is a common malignancy with approximately 600 000 new cases yearly. Disappointingly, the overall survival has not increased over the last decades. The concept of personalized medicine, i.e. to treat every patient with an individually planned treatment regime has gathered increased interest, but requires the establishment of novel biomarkers that can predict treatment response.

The aim of this thesis is to propose novel predictive single markers or combinations of markers of response to radiation, cisplatin and cetuximab. The general methodology is to evaluate common differences of cell lines resistant to radiation, cisplatin or cetuximab compared to sensitive counterparts.

In paper I, we analysed the expression of 14 proteins involved in growth control and/or apoptosis by western blot and related them to intrinsic radiosensitivity (IR) in nine cell lines. No factor had a significant correlation to IR on its own. A combination of EGFR, survivin, Bak, Smad4, and Hsp70 had the best correlation to IR (R=0.886, p=0.001). Additionally, we analysed the presence of p53 mutations in the cell lines. All cell lines had at least one missense, splice site or loss of transcript mutation. To be able to combine protein expression and presence of p53 mutations we created a system designated the number of negative points (NNP). With this system we could extract that expression of EGFR, survivin, and p53 missense or splice site mutations had the best correlation to IR (R=0.990, p<0.001).

In paper II we conducted a gene expression microarray analysis of three cell lines, from which common deregulations in two cisplatin resistant cell lines was compared to a cisplatin sensitive cell line. From a bioinformatic approach of gene ontology and molecular network analysis, we defined a transcriptional profile of 20 genes. Finally, key findings were analysed in a larger panel of cell lines, where high MMP-7 expression correlated with higher cisplatin resistance.

Paper III compared 4 cell lines with high IR to a radiosensitive equivalent. Using a similar bioinformatic approach as paper II, we established a transcriptional profile of 14 genes. Analysis in a larger panel of cell lines revealed that FN1 expression predicts higher IR.

Paper IV establishes the cetuximab sensitivity of 35 cell lines of which 12 were resistant and five were sensitive to cetuximab. After whole genome gene copy number analysis of five cetuximab resistant and five cetuximab sensitive cell lines, and verification of key findings in a larger cell line panel, the results show that the amplification of the YAP1 gene is coupled to cetuximab resistance.

In summary, this thesis proposes a number of novel markers of resistance to radiation, cisplatin, and cetuximab which could influence treatment choice in the future, following verifications in primary tumor material.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2012. 83 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1291
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-76152 (URN)978-91-7519-968-9 (ISBN)
Public defence
2012-04-27, Elsa Brändströmsalen, Campus US, Linköpings universitet, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2012-03-29 Created: 2012-03-29 Last updated: 2012-03-29Bibliographically approved

Open Access in DiVA

No full text

Authority records BETA

Jerhammar, FredrikJohansson, Ann-CharlotteJansson, AgnetaWelander, JennySöderkvist, PeterRoberg, Karin

Search in DiVA

By author/editor
Jerhammar, FredrikJohansson, Ann-CharlotteJansson, AgnetaWelander, JennySöderkvist, PeterRoberg, Karin
By organisation
Oto-Rhiono-Laryngology and Head & Neck SurgeryFaculty of Health SciencesExperimental PathologyOncologyCell BiologyDepartment of ENT - Head and Neck Surgery UHL
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar

urn-nbn

Altmetric score

urn-nbn
Total: 426 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf