title: FGFR1 Is a Potential Prognostic Biomarker and Therapeutic Target in Head and Neck Squamous Cell Carcinoma.
abstract: FGFR1 is a promising therapeutic target in multiple types of solid tumors, including head and neck squamous cell carcinoma (HNSCC). FGFR inhibitors have shown great therapeutic value in preclinical models. However, resistance remains a major setback. In this study, we have investigated the prognostic value of FGFR1 expression in HNSCC, the therapeutic relevance of targeting FGFR with AZD4547, and potential resistant mechanisms.
  
  
  
  IHC and FISH were applied on tissue microarrays to investigate FGFR1 protein expression and FGFR1 gene copy numbers in 452 HNSCCs. The sensitivity of HNSCC cell lines to AZD4547, either as single or combination treatment with the EGFR inhibitor gefitinib, was assessed using long-term colony formation assays, short-term viability assays, and biochemical analysis.
  
  
  
  FGFR1 protein overexpression occurred in 82% (36/44) of human papillomavirus (HPV)-positive HNSCC and 75% (294/392) of HPV-negative HNSCC and relates with poor overall survival and disease-free survival in HPV-negative HNSCC [HR, 3.07; 95% confidence interval (CI), 1.74-6.90; P = 0.001 and HR, 1.53; 95% CI, 1.04-2.39; P = 0.033]. Moreover, the FGFR1 gene was amplified in 3% (3/110) of HPV-negative HNSCC. Treatment of the high FGFR1-expressing cell line CCL30 with AZD4547 reduced cell proliferation and FGFR signaling. Two FGFR-amplified cell lines, SCC147 and BICR16, were resistant to AZD4547 treatment due to EGFR signaling. Combined AZD4547 and gefitinib treatment synergistically inhibited the proliferation of resistant cell lines.
  
  
  
  Here, we identify high FGFR1 expression as a candidate prognostic biomarker in HPV-negative HNSCC. Furthermore, we provide a rationale for treating FGFR1-expressing HNSCC with the FGFR inhibitor AZD4547 and for combining AZD4547 and gefitinib in FGFR inhibitor-resistant HNSCC patients. Clin Cancer Res; 22(15); 3884-93. ©2016 AACR.
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands. Department of Head and Neck Surgical Oncology, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Koos
authors.initials: K
authors.lastname: Koole
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Diede
authors.initials: D
authors.lastname: Brunen
authors.affiliation: Department of Otorhinolaryngology - Head and Neck Surgery, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Pauline M W
authors.initials: PM
authors.lastname: van Kempen
authors.affiliation: Department of Head and Neck Surgical Oncology, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Noorlag
authors.affiliation: Department of Head and Neck Surgical Oncology, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Remco
authors.initials: R
authors.lastname: de Bree
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Cor
authors.initials: C
authors.lastname: Lieftink
authors.affiliation: Department of Head and Neck Surgical Oncology, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Robert J J
authors.initials: RJ
authors.lastname: van Es
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: René
authors.initials: R
authors.lastname: Bernards
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands. Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands. s.m.willems-4@umcutrecht.nl.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Willems
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005260:Female; D000077156:Gefitinib; D005784:Gene Amplification; D015870:Gene Expression; D006258:Head and Neck Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D011379:Prognosis; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: C572463:AZD4547; D000970:Antineoplastic Agents; D001549:Benzamides; D014408:Biomarkers, Tumor; D010879:Piperazines; D011720:Pyrazoles; D011799:Quinazolines; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D000077156:Gefitinib