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.
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.
Authors: Benedikt Kramer; Johannes David Schultz; Clemens Hock; Alexander Sauter; Boris A Stuck; Karl Hörmann; Richard Birk; Christoph Aderhold Journal: Oncol Lett Date: 2017-03-13 Impact factor: 2.967
Authors: Martina Raudenska; Marketa Sztalmachova; Jaromir Gumulec; Michaela Fojtu; Hana Polanska; Jan Balvan; Marek Feith; Hana Binkova; Zuzana Horakova; Rom Kostrica; Rene Kizek; Michal Masarik Journal: Tumour Biol Date: 2015-07-14
Authors: Md Almamun; Benjamin T Levinson; Annette C van Swaay; Nathan T Johnson; Stephanie D McKay; Gerald L Arthur; J Wade Davis; Kristen H Taylor Journal: Epigenetics Date: 2015 Impact factor: 4.528
Authors: Marketa Svobodova; Martina Raudenska; Jaromir Gumulec; Jan Balvan; Michaela Fojtu; Monika Kratochvilova; Hana Polanska; Zuzana Horakova; Rom Kostrica; Petr Babula; Zbynek Heger; Michal Masarik Journal: Oncotarget Date: 2017-08-03