Proteomic profiling identifies PTK2/FAK as a driver of radioresistance in HPV-negative head and neck cancer

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

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20 Scopus citations

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-Marrest 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 HPVnegative 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.

Original languageEnglish (US)
Pages (from-to)4643-4650
Number of pages8
JournalClinical Cancer Research
Volume22
Issue number18
DOIs
StatePublished - Sep 15 2016

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Skinner, H. D., Giri, U., Yang, L., Woo, S. H., Story, M. D., Pickering, C. R., Byers, L. A., Williams, M. D., El-Naggar, A., Wang, J., Diao, L., Shen, L., Fan, Y. H., Molkentine, D. P., Beadle, B. M., Meyn, R. E., Myers, J. N., & Heymach, J. V. (2016). Proteomic profiling identifies PTK2/FAK as a driver of radioresistance in HPV-negative head and neck cancer. Clinical Cancer Research, 22(18), 4643-4650. https://doi.org/10.1158/1078-0432.CCR-15-2785