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RNAscope for In situ Detection of Transcriptionally Active Human Papillomavirus in Head and Neck Squamous Cell Carcinoma
Published on: March 11, 2014
Increased Expression of HER2, HER3, and HER2:HER3 Heterodimers in HPV-Positive HNSCC Using a Novel Proximity-Based
Netanya I Pollock1, Lin Wang1, Gerald Wallweber2
1University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Purpose:
In other cancer types, HPV infection has been reported to coincide with overexpression of HER2 (ERBB2) and HER3 (ERBB3); however, the association between HER2 or HER3 expression and dimer formation in HNSCC has not been reported. Overexpression of HER2 and HER3 may contribute to resistance to EGFR inhibitors, including cetuximab, although the contribution of HPV in modulating cetuximab response remains unknown. Determination of heterodimerization of HER receptors is challenging and has not been reported in HNSCC. The present study aimed to determine the expression of HER proteins in HPV(+) versus HPV(-) HNSCC tumors using a proximity-based protein expression assay (VeraTag), and to determine the efficacy of HER-targeting agents in HPV(+) and HPV(-) HNSCC cell lines.
Experimental Design:
Expression of total HER1, HER2, and HER3, p95HER2, p-HER3, HER1:HER1 homodimers, HER2:HER3 heterodimers, and the HER3-PI3K complex in 88 HNSCC was determined using VeraTag, including 33 baseline tumors from individuals treated in a trial including cetuximab. Inhibition of cell growth and protein activation with cetuximab and afatinib was compared in HPV(+) and HPV(-) cetuximab-resistant cell lines.
Results:
Expression of total HER2, total HER3, HER2:HER3 heterodimers, and the HER3:PI3K complex were significantly elevated in HPV(+) HNSCC. Total EGFR was significantly increased in HPV(-) HNSCC where VeraTag assay results correlated with IHC. Afatinib significantly inhibited cell growth when compared with cetuximab in the HPV(+) and HPV(-) cetuximab-resistant HNSCC cell lines.
Conclusions:
These findings suggest that agents targeting multiple HER proteins may be effective in the setting of HPV(+) HNSCC and/or cetuximab resistance.
Insights
Human papillomavirus (HPV) positive head and neck squamous cell carcinoma (HNSCC) shows increased HER2 and HER3 expression and dimers. Targeting multiple HER proteins may overcome cetuximab resistance in HPV(+) HNSCC.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Human papillomavirus (HPV) infection is linked to Human Epidermal growth factor Receptor (HER) overexpression in some cancers.
- The role of HER2 and HER3 expression and dimerization in HPV-associated head and neck squamous cell carcinoma (HNSCC) remains unclear.
- Understanding HER receptor dynamics is crucial for predicting response to Epidermal Growth Factor Receptor (EGFR) inhibitors like cetuximab.
Purpose of the Study:
- To investigate HER protein expression and dimerization in HPV(+) versus HPV(-) HNSCC.
- To evaluate the efficacy of HER-targeting agents in HPV(+) and HPV(-) HNSCC cell lines.
- To explore the association between HPV status, HER expression, and cetuximab resistance.
Main Methods:
- Utilized the VeraTag proximity-based assay to quantify HER1, HER2, HER3, dimers (HER1:HER1, HER2:HER3), and HER3-PI3K complex in 88 HNSCC tumors.
- Analyzed 33 tumors from a cetuximab treatment trial.
- Compared cell growth inhibition and protein activation by cetuximab and afatinib in HPV(+) and HPV(-) cetuximab-resistant HNSCC cell lines.
Main Results:
- Significantly elevated levels of HER2, HER3, HER2:HER3 heterodimers, and HER3:PI3K complex were observed in HPV(+) HNSCC.
- HPV(-) HNSCC showed significantly increased total EGFR expression.
- Afatinib demonstrated superior inhibition of cell growth compared to cetuximab in both HPV(+) and HPV(-) cetuximab-resistant HNSCC cell lines.
Conclusions:
- Findings indicate that targeting multiple HER proteins could be a promising strategy for HPV(+) HNSCC.
- This approach may also be effective in overcoming cetuximab resistance in HNSCC.
- HER dimerization assays provide valuable insights into HNSCC biology and treatment response.
