Heat shock protein 90 (HSP90) is overexpressed in p16-negative oropharyngeal squamous cell carcinoma, and its inhibition in vitro potentiates the effects of chemoradiation.

Abstract

PURPOSE:

Cisplatin and radiation therapy remain the current standard for treating locally advanced SCCHN. Novel treatment approaches are needed, especially in patients with human papilloma virus (HPV)-negative disease who have worse outcomes despite multimodality therapy.

METHODS:

Using our institutional review board approved database, we obtained twenty oropharyngeal squamous cell carcinoma (SCC) tissue samples: ten p16 positive, ten p16-negative. Because p16 expression is strongly associated with HPV positivity in oropharyngeal SCC, p16 status was used as a marker of HPV. We subsequently analyzed, via immunohistochemistry, heat shock protein 90 (HSP90) protein levels. Using HPV-positive and HPV-negative SCC cell lines, we compared baseline HSP90 expression levels and the effect of the HSP90 inhibitor ganetespib on viability and apoptosis. Clonogenic survival of HPV-negative cells treated with ganetespib, radiation therapy, and/or cisplatin was then investigated. We characterize the effects of ganetespib on proteins that are thought to drive DNA damage resistance in HPV-negative cells.

RESULTS:

HSP90 expression was significantly higher in p16-negative compared with p16-positive samples (p = 0.016) and in HPV-negative cell lines compared with positive cells. Ganetespib increased cytotoxicity and induced apoptosis in HPV-negative more than positive cells. Adding ganetespib to cisplatin and/or radiation therapy in HPV-negative cells further decreased clonogenic survival. Finally, ganetespib downregulated expressions of EGFR, ERK, AKT, p53, and HIF-1α.

CONCLUSIONS:

Ganetespib inhibited HPV-negative SCCHN viability and potentiated cell kill when combined with cisplatin or radiation therapy in vitro. With HSP90 expression higher in HPV-negative cells and in p16-negative patients, further exploration of the clinical activity of HSP90 inhibitors in SCCHN is warranted.

• Authors: Kirtesh Patel, Jing Wen, Kelly Magliocca, Susan Muller, Yuan Liu, Zhuo Georgia Chen, Nabil Saba, Roberto Diaz
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 74 Issue 5 Pg. 1015-22 (Nov 2014) ISSN: 1432-0843 [Electronic] Germany
• PMID: 25205430 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Cyclin-Dependent Kinase Inhibitor p16
• HSP90 Heat-Shock Proteins
• Hypoxia-Inducible Factor 1, alpha Subunit
• STA 9090
• Triazoles
• Deferoxamine
• Cisplatin

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects, radiation effects)
• Blotting, Western
• Carcinoma, Squamous Cell (metabolism, pathology, virology)
• Cell Hypoxia
• Cell Line, Tumor
• Cell Proliferation (drug effects, radiation effects)
• Cell Survival (drug effects, radiation effects)
• Cisplatin (pharmacology)
• Cyclin-Dependent Kinase Inhibitor p16 (metabolism)
• Deferoxamine (pharmacology)
• Dose-Response Relationship, Drug
• Dose-Response Relationship, Radiation
• Female
• HSP90 Heat-Shock Proteins (antagonists & inhibitors, metabolism)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Immunohistochemistry
• Male
• Oropharyngeal Neoplasms (metabolism, pathology, virology)
• Papillomaviridae (physiology)
• Triazoles (pharmacology)