Activation of fibroblast growth factor receptor (FGFR) signaling occurs in various cancers, including esophageal squamous cell carcinoma (ESCC), however, the effect of targeting FGFR in ESCC is not clear. Herein, we examined the phosphorylation level of FGFR1Y654 (p‑FGFR1) in ESCC cell lines and tumor tissues, as well as the cancer cell killing effects of gefitinib and FGFR inhibitor AZD4547 in combination form or alone in ESCC cells. Immunohistochemistry staining was used to detect the expression level of p‑FGFR1 in 87 ESCC specimens. The effects of gefitinib and FGFR inhibitor AZD4547 on ESCC cells were analyzed by CCK‑8 assay, flow cytometry and western blotting assays. Twenty‑six patients diagnosed with esophageal squamous cell carcinoma (ESCC) (29.9%) were observed with a high level of p‑FGFR1. The proportion of lesions located in the lower segment of the esophagus was significantly higher in the high p‑FGFR1 level group (26.9 vs. 8.2%, P=0.003). The IC50 values of gefitinib alone and in combination with 500 nM AZD4547 were 22.9±2.1 and 4.13±0.12 µM in TE10 cells, and 9.85±5.5 and 3.21±0.76 µM in EC9706 cells, respectively. The combination of AZD4547 and gefitinib induced robust apoptosis and decreased clone formation ability compared to gefitinib monotherapy in the TE10 cells. TE10 cells exhibited a mesenchymal phenotype, with a higher level of p‑FGFR1 and p‑AKT than that in EC9706 cells. AZD4547 and gefitinib co‑treatment resulted in a significant decrease in the level of p‑AKT in TE10 cells and a complete inhibition of phosphorylation of ERK1/2 in EC9706 cells. Collectively, AZD4547 can improve sensitivity of ESCC cells to gefitinib.
Radiotherapy has an important role in the comprehensive treatment of breast cancer. However, the clinical outcome of adjuvant radiotherapy may be limited due to intrinsic radioresistance, it is necessary to explore efficient radiosensitization methods that improve the clinical outcome of patients undergoing radiotherapy. The present study aimed to investigate whether the novel mechanistic target of rapamycin (mTOR) inhibitor Torin2 enhances the radiosensitivity of MCF‑7 breast cancer cells. A Cell Counting Kit‑8 (CCK‑8) assay was performed to measure the effect of Torin2 on cell proliferation, while clonogenic assays were employed to determine the effect of Torin2 in combination with radiation on the proliferation of MCF‑7 cells. The effect of Torin2 and/or radiation on the cell cycle was analyzed using flow cytometry. Furthermore, the protein expression of components of the phosphatidylinositol 3‑kinase/Akt/mTOR pathway, and the expression of proteins involved in DNA damage repair, was measured by western blot analysis. The results demonstrated that Torin2 exhibited a higher potency in MCF‑7 cells, while MDA‑MB‑231 cells were less sensitive to Torin2. Compared with irradiation alone, pretreatment with 20 nM Torin2 followed by irradiation resulted in an increased level of γ‑H2A histone family member X. Radiation induced the activation of the Akt/mTOR signaling pathway and upregulated the expression of phosphorylated (p)‑Akt473 and p‑eukaryotic translation initiation factor 4E binding protein 1 (4EBP1)37/46. Notably, pretreatment with Torin2 attenuated the radiation‑induced activation of the Akt/mTOR signaling pathway. In addition, Torin2 partially blocked the repair of double‑strand breaks induced by radiation by reducing the activation of ataxia telangiectasia‑mutated, and sensitized MCF‑7 cells to radiation. In conclusion, administration of Torin2 prior to irradiation enhanced the radiotherapeutic effect on breast cancer cells in vitro, and these results may provide a foundation for the rational use of combined therapy with irradiation and Torin2 for breast cancer in clinical practice.
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