title: FLT1 kinase is a mediator of radioresistance and survival in head and neck squamous cell carcinoma.
abstract: Head and neck squamous cell carcinoma (HNSCC) is the fifth most common malignancy worldwide, responsible for approximately half a million new cases every year. The treatment of this disease is challenging and characterised by high rates of therapy failure and toxicity, stressing the need for new innovative treatment strategies.
  
  
  METHODS
  In this study we performed a shRNAmir-based screen on HNSCC cells with the aim to identify tyrosine kinases that are mediating radiotherapy resistance.
  
  
  RESULTS
  The receptor tyrosine kinase FLT1 (VEGFR1) was identified as an important driver of cell survival and radioresistance. We show that FLT1 is phosphorylated in HNSCC cells, and document autocrine production of FLT1 ligands VEGFA and VEGFB, leading to receptor activation. Immunohistochemistry on HNSCC patient samples demonstrated FLT1 and VEGFA to be uniformly expressed. Interestingly, FLT1 was selectively overexpressed in tumour tissue as compared to non-cancerous epithelium. Remarkably, we found only membrane permeable FLT1 kinase inhibitors to be effective, which was in agreement with the intracellular localisation of FLT1.
  
  
  CONCLUSIONS
  Taken together, we document expression of FLT1 in HNSCC and demonstrate this kinase to modulate radioresistance and cancer cell survival. Given the fact that FLT1 kinase is selectively upregulated in tumour tissue and that its kinase function seems expendable for normal life and development, this kinase holds great promise as a new potential therapeutic target.
authors.affiliation: Department of Radiation Oncology , UH Leuven, Leuven , Belgium.
authors.forename: Evert Jan
authors.initials: EJ
authors.lastname: Van Limbergen
authors.forename: Piotr
authors.initials: P
authors.lastname: Zabrocki
authors.forename: Michaël
authors.initials: M
authors.lastname: Porcu
authors.forename: Esther
authors.initials: E
authors.lastname: Hauben
authors.forename: Jan
authors.initials: J
authors.lastname: Cools
authors.forename: Sandra
authors.initials: S
authors.lastname: Nuyts
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000401:mortality / Q000532:radiotherapy; D045744:Cell Line, Tumor; D006258:Head and Neck Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000532:radiotherapy; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D018613:Microscopy, Confocal; D011836:Radiation Tolerance / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D000077195:Squamous Cell Carcinoma of Head and Neck; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1