Proteomic Profiling Identifies PTK2/FAK as a Driver of Radioresistance in HPV-negative Head and Neck Cancer.

Abstract

PURPOSE:

Head and neck squamous cell carcinoma (HNSCC) is commonly treated with radiotherapy, and local failure after treatment remains the major cause of disease-related mortality. To date, human papillomavirus (HPV) is the only known clinically validated, targetable biomarkers of response to radiation in HNSCC.

EXPERIMENTAL DESIGN:

We performed proteomic and transcriptomic analysis of targetable biomarkers of radioresistance in HPV-negative HNSCC cell lines in vitro, and tested whether pharmacologic blockade of candidate biomarkers sensitized cells to radiotherapy. Candidate biomarkers were then investigated in several independent cohorts of patients with HNSCC.

RESULTS:

Increased expression of several targets was associated with radioresistance, including FGFR, ERK1, EGFR, and focal adhesion kinase (FAK), also known as PTK2. Chemical inhibition of PTK2/FAK, but not FGFR, led to significant radiosensitization with increased G2-M arrest and potentiated DNA damage. PTK2/FAK overexpression was associated with gene amplification in HPV-negative HNSCC cell lines and clinical tumors. In two independent cohorts of patients with locally advanced HPV-negative HNSCC, PTK2/FAK amplification was highly associated with poorer disease-free survival (DFS; P = 0.012 and 0.034). PTK2/FAK mRNA expression was also associated with worse DFS (P = 0.03). Moreover, both PTK2/FAK mRNA (P = 0.021) and copy number (P = 0.063) were associated with DFS in the Head and Neck Cancer subgroup of The Cancer Genome Atlas.

CONCLUSIONS:

Proteomic analysis identified PTK2/FAK overexpression is a biomarker of radioresistance in locally advanced HNSCC, and PTK2/FAK inhibition radiosensitized HNSCC cells. Combinations of PTK2/FAK inhibition with radiotherapy merit further evaluation as a therapeutic strategy for improving local control in HPV-negative HNSCC. Clin Cancer Res; 22(18); 4643-50. ©2016 AACR.

• Authors: Heath D Skinner, Uma Giri, Liang Yang, Sang Hyeok Woo, Michael D Story, Curtis R Pickering, Lauren A Byers, Michelle D Williams, Adel El-Naggar, Jing Wang, Lixia Diao, Li Shen, You Hong Fan, David P Molkentine, Beth M Beadle, Raymond E Meyn, Jeffrey N Myers, John V Heymach
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 22 Issue 18 Pg. 4643-50 (Sep 15 2016) ISSN: 1557-3265 [Electronic] United States
• PMID: 27036135 (Publication Type: Journal Article)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Biomarkers, Tumor
• Proteome
• Focal Adhesion Kinase 1
• PTK2 protein, human

Topics

• Biomarkers, Tumor
• Cell Line, Tumor
• DNA Damage
• Focal Adhesion Kinase 1 (genetics, metabolism)
• Gene Dosage
• Gene Expression
• Head and Neck Neoplasms (etiology, metabolism, radiotherapy)
• Humans
• Proteome
• Proteomics (methods)
• Radiation Tolerance (genetics)
• Treatment Outcome