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

Research output: Contribution to journalArticle

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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-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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Focal Adhesion Protein-Tyrosine Kinases
Head and Neck Neoplasms
Proteomics
Biomarkers
Radiotherapy
Carcinoma, squamous cell of head and neck
Messenger RNA
Gene Amplification
Atlases
Tumor Cell Line
Treatment Failure
DNA Damage
Disease-Free Survival
Neoplasms
Research Design
Genome
Radiation
Cell Line
Mortality

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Proteomic profiling identifies PTK2/FAK as a driver of radioresistance in HPV-negative head and neck cancer. / Skinner, Heath D.; Giri, Uma; Yang, Liang; Woo, Sang Hyeok; Story, Michael D.; Pickering, Curtis R.; Byers, Lauren A.; Williams, Michelle D.; El-Naggar, Adel; Wang, Jing; Diao, Lixia; Shen, Li; Fan, You Hong; Molkentine, David P.; Beadle, Beth M.; Meyn, Raymond E.; Myers, Jeffrey N.; Heymach, John V.

In: Clinical Cancer Research, Vol. 22, No. 18, 15.09.2016, p. 4643-4650.

Research output: Contribution to journalArticle

Skinner, HD, Giri, U, Yang, L, Woo, SH, Story, MD, Pickering, CR, Byers, LA, Williams, MD, El-Naggar, A, Wang, J, Diao, L, Shen, L, Fan, YH, Molkentine, DP, Beadle, BM, Meyn, RE, Myers, JN & Heymach, JV 2016, 'Proteomic profiling identifies PTK2/FAK as a driver of radioresistance in HPV-negative head and neck cancer', Clinical Cancer Research, vol. 22, no. 18, pp. 4643-4650. https://doi.org/10.1158/1078-0432.CCR-15-2785
Skinner, Heath D. ; Giri, Uma ; Yang, Liang ; Woo, Sang Hyeok ; Story, Michael D. ; Pickering, Curtis R. ; Byers, Lauren A. ; Williams, Michelle D. ; El-Naggar, Adel ; Wang, Jing ; Diao, Lixia ; Shen, Li ; Fan, You Hong ; Molkentine, David P. ; Beadle, Beth M. ; Meyn, Raymond E. ; Myers, Jeffrey N. ; Heymach, John V. / Proteomic profiling identifies PTK2/FAK as a driver of radioresistance in HPV-negative head and neck cancer. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 18. pp. 4643-4650.
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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-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.",
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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.

PY - 2016/9/15

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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.

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