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FLT1 kinase is a mediator of radioresistance and survival in head and neck squamous cell carcinoma.
Van Limbergen, Evert Jan; Zabrocki, Piotr; Porcu, Michaël; Hauben, Esther; Cools, Jan; Nuyts, Sandra.
Afiliação
  • Van Limbergen EJ; Department of Radiation Oncology , UH Leuven, Leuven , Belgium.
Acta Oncol ; 53(5): 637-45, 2014 May.
Article em En | MEDLINE | ID: mdl-24041258
UNLABELLED: 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. MATERIAL AND 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. DISCUSSION AND CONCLUSION: 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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tolerância a Radiação / Carcinoma de Células Escamosas / Receptor 1 de Fatores de Crescimento do Endotélio Vascular / Neoplasias de Cabeça e Pescoço Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2014 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tolerância a Radiação / Carcinoma de Células Escamosas / Receptor 1 de Fatores de Crescimento do Endotélio Vascular / Neoplasias de Cabeça e Pescoço Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2014 Tipo de documento: Article