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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.​ 

Author information​

Skinner HD1, Giri U2, Yang L3, Woo SH3, Story MD4, Pickering CR5, Byers LA2, Williams MD6, El-Naggar A6, Wang J7, Diao L7, Shen L7, Fan YH7, Molkentine DP3, Beadle BM8, Meyn RE3, Myers JN5, Heymach JV2.

1Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. hskinner@mdanderson.org.

2Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

3Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

4Department of Radiation Oncology, The University of Texas Southwestern Medical Center and Simmons Comprehensive Cancer Center, Dallas, Texas.

5Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.

6Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

7Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.

8Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.