TY - JOUR
T1 - Proteomic profiling identifies PTK2/FAK as a driver of radioresistance in HPV-negative head and neck cancer
AU - Skinner, Heath D.
AU - Giri, Uma
AU - Yang, Liang
AU - Woo, Sang Hyeok
AU - Story, Michael D.
AU - Pickering, Curtis R.
AU - Byers, Lauren A.
AU - Williams, Michelle D.
AU - El-Naggar, Adel
AU - Wang, Jing
AU - Diao, Lixia
AU - Shen, Li
AU - Fan, You Hong
AU - Molkentine, David P.
AU - Beadle, Beth M.
AU - Meyn, Raymond E.
AU - Myers, Jeffrey N.
AU - Heymach, John V.
N1 - Funding Information:
This work was supported by the following grants from the NCI (NIH): R01 CA 168484-022 (to J.V. Heymach), HNSCC SPORE 5 P50CA070907-16 (to J.V. Heymach and J.N. Myers), CCSG 5 P30 CA01667239 (to J.V. Heymach), and R01 CA 168485 (to R.E. Meyn). This work was also supported by the Cancer Prevention Institute of Texas (RP150293; to H.D. Skinner). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
©2016 American Association for Cancer Research.
PY - 2016/9/15
Y1 - 2016/9/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84990940876&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84990940876&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-15-2785
DO - 10.1158/1078-0432.CCR-15-2785
M3 - Article
C2 - 27036135
AN - SCOPUS:84990940876
SN - 1078-0432
VL - 22
SP - 4643
EP - 4650
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 18
ER -