The Application of ATR Kinase Inhibitor AZD6738 in Combination with Radiotherapy for the Treatment of Melanoma

BACKGROUND: Melanoma is categorized as one of the most malignant, severe, and lethal cancers of the skin. Regarding the lack of efficiency of conventional therapies for most patients, novel therapeutic strategies are strongly required. OBJECTIVE: The current study aimed to assess the impact of AZD6738- an ATR kinase inhibitor- in combination with 6 MV X-ray on the human melanoma cell line (A375). MATERIAL AND METHODS: In this experimental study, cells were treated with different concentrations of AZD6738 for 24 and 48 h in the presence and absence of radiation (2 Gy, 4 Gy, and 6 Gy). The cell viability and cell proliferation assay were examined in both experimental and control groups by MTT and colony formation techniques, respectively. RESULTS: The results indicated that by increasing the concentration of AZD6738, the cell viability was markedly diminished in all treatment groups. As expected, the cell viability of the cells treated with AZD6738 and radiation was significantly lower than the group treated with AZD6738 alone. Besides, the combinatory treatment significantly decreased cell proliferation in the melanoma cell line. The combination of AZD6738 with radiation resulted in a significant increase in cytotoxicity by a 50% increase in cell death when used at concentrations of 0.3 µM, 1 µM, 1.51 µM, and 1.61 µM, respectively. CONCLUSION: The combination of AZD6738 with radiation possesses a synergistic effect on the reduction of the cell viability and proliferation of melanoma cells. This present study provides insight into the impact of Ataxia Telangiectasia and Rad3-related kinase (ATR) inhibition on the potential role of this kinase in the suppression of melanoma cell proliferation.