Department of Molecular Biology and Genetics, Erzurum Technical University, Omer Nasuhi Bilmen Mah. Havaalani Yolu Cad. No: 53 Yakutiye, Erzurum, Turkey.
Molecular Cancer Biology Laboratory, High Technology Application and Research Center, Erzurum Technical University, Erzurum, Turkey.
Cell Oncol (Dordr). 2022 Feb;45(1):41-56. doi: 10.1007/s13402-021-00645-6. Epub 2021 Nov 27.
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.
化疗耐药性的发展是头颈部鳞状细胞癌（HNSCC）治疗的主要障碍之一。参与耐药性的 PI3K/Akt 通路在超过 90%的 HNSCC 中被发现过度激活。据报道，FGFR（成纤维细胞生长因子受体）的异常激活导致 PI3K/Akt 通路的过度激活，并与干细胞特征的维持有关，这是通过 SOX2 表达来控制的。在这项研究中，我们旨在研究使用口服生物可利用的 FGFR 抑制剂 AZD4547 通过靶向 FGFR/Akt/SOX2 轴来克服紫杉醇耐药性的潜力在 HNSCC 中。
我们最初使用计算机工具评估 FGFR2 和 SOX2 的表达。我们分析了正常/肿瘤组织对和重组 FGF2 处理的 HNSCC 细胞中的 FGFR/Akt/SOX2 轴。接下来，我们使用体外模型探索了 AZD4547 单独和与紫杉醇联合对亲本/紫杉醇耐药细胞的增殖、迁移和集落形成能力的影响。
我们发现肿瘤组织中的 p-FGFR、p-AKT、p-GSK-3β 和 SOX2 表达水平高于其相应的正常组织，并且 AZD4547 有效地抑制了重组 FGF2 处理的 HNSCC 细胞中 FGFR 及其下游靶标的表达。我们还发现，AZD4547 降低了 HNSCC 细胞的活力、迁移和集落形成能力，并且紫杉醇联合治疗增强了紫杉醇对这些细胞的影响。最后，我们发现 AZD4547 抑制了过表达的 FGFR/Akt/SOX2 轴，并在紫杉醇耐药的 HNSCC 细胞中显著抑制了与癌症相关的表型。
从我们的数据中我们得出结论，AZD4547 可能会增加紫杉醇在 HNSCC 治疗中的作用。我们建议将 AZD4547 作为一种治疗剂来克服紫杉醇耐药性。
