title: Proteomic Profiling Identifies PTK2/FAK as a Driver of Radioresistance in HPV-negative Head and Neck Cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.affiliation: Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. hskinner@mdanderson.org.
authors.forename: Heath D
authors.initials: HD
authors.lastname: Skinner
authors.affiliation: Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Uma
authors.initials: U
authors.lastname: Giri
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Liang
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Sang Hyeok
authors.initials: SH
authors.lastname: Woo
authors.affiliation: Department of Radiation Oncology, The University of Texas Southwestern Medical Center and Simmons Comprehensive Cancer Center, Dallas, Texas.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Story
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Curtis R
authors.initials: CR
authors.lastname: Pickering
authors.affiliation: Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Byers
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Williams
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Adel
authors.initials: A
authors.lastname: El-Naggar
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Lixia
authors.initials: L
authors.lastname: Diao
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: You Hong
authors.initials: YH
authors.lastname: Fan
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: David P
authors.initials: DP
authors.lastname: Molkentine
authors.affiliation: Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Beth M
authors.initials: BM
authors.lastname: Beadle
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Raymond E
authors.initials: RE
authors.lastname: Meyn
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Myers
authors.affiliation: Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: John V
authors.initials: JV
authors.lastname: Heymach
mesh_terms: D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D004249:DNA Damage; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism*; D018628:Gene Dosage; D015870:Gene Expression; D006258:Head and Neck Neoplasms / Q000209:etiology / Q000378:metabolism* / Q000532:radiotherapy; D006801:Humans; D020543:Proteome; D040901:Proteomics / Q000379:methods; D011836:Radiation Tolerance / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D020543:Proteome; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human