AZD4547 targets the FGFR/Akt/SOX2 axis to overcome paclitaxel resistance in head and neck cancer
Autor: | Michael Ittmann, Neslisah Barlak, Betul Gundogdu, Omer Faruk Karatas, Abdulmelik Aytatli, Hasan Onur Caglar, Arzu Tatar, Fatma Sanli |
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Rok vydání: | 2021 |
Předmět: |
Cancer Research
Paclitaxel Fibroblast growth factor Piperazines Phosphatidylinositol 3-Kinases stomatognathic system SOX2 Cell Line Tumor medicine Humans Receptor Protein kinase B PI3K/AKT/mTOR pathway Cell Proliferation Glycogen Synthase Kinase 3 beta Chemistry SOXB1 Transcription Factors General Medicine medicine.disease Receptors Fibroblast Growth Factor Head and neck squamous-cell carcinoma stomatognathic diseases Oncology Drug Resistance Neoplasm Head and Neck Neoplasms Fibroblast growth factor receptor Benzamides embryonic structures Cancer research Pyrazoles Molecular Medicine biological phenomena cell phenomena and immunity Stem cell Proto-Oncogene Proteins c-akt |
Zdroj: | Cellular Oncology. 45:41-56 |
ISSN: | 2211-3436 2211-3428 |
Popis: | Development of chemoresistance is one of the major obstacles to the treatment of head and neck squamous cell carcinoma (HNSCC). The PI3K/Akt pathway, involved in drug resistance, has been found to be overactivated in > 90% of HNSCCs. Aberrant activation of the FGF receptors (FGFRs) has been reported to cause overactivation of the PI3K/Akt pathway and to be associated with the maintenance of stem cell features, which is controlled via SOX2 expression. In this study, we aimed at investigating the potential of using AZD4547, an orally bioavailable FGFR inhibitor, to overcome taxol-resistance by targeting the FGFR/Akt/SOX2 axis in HNSCC. We initially evaluated FGFR2 and SOX2 expression using in silico tools. We analyzed the FGFR/Akt/SOX2 axis in normal/tumor tissue pairs and in recombinant FGF2 treated HNSCC cells. Next, we explored the effects of AZD4547 alone and in combination with taxol on the proliferation, migration and colony forming capacities of parental/taxol-resistant cells using in vitro models. We found that the p-FGFR, p-AKT, p-GSK-3β and SOX2 expression levels were higher in tumor tissues than in its corresponding normal tissues, and that AZD4547 effectively suppressed the expression of FGFR and its downstream targets in recombinant FGF2 treated HNSCC cells. We also found that AZD4547 diminished the viability, migration and colony forming capacity of HNSCC cells, and that co-treatment with taxol potentiated the impact of taxol on these cells. Finally, we found that AZD4547 inhibited the overexpressed FGFR/Akt/SOX2 axis and profoundly suppressed cancer-related phenotypes in taxol-resistant HNSCC cells. From our data we conclude that AZD4547 may increase the impact of taxol during HNSCC treatment. We suggest AZD4547 as a therapeutic agent to overcome taxol-resistance. |
Databáze: | OpenAIRE |
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