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Purpose: 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., Methods: 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., Results: 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., Conclusion: 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., (© 2021. Springer Nature Switzerland AG.)