As a selective inhibitor of BRAF kinase, dabrafenib has shown potent anti‐tumour activities in patients with BRAFV600E mutant anaplastic thyroid cancer. However, the resistance of thyroid cancer cells to dabrafenib limited its therapeutic effect. The effects of melatonin and dabrafenib as monotherapy or in combination on the proliferation, cell cycle arrest, apoptosis, migration and invasion of anaplastic thyroid cancer cells were examined. The molecular mechanism involved in drug combinations was also revealed. Melatonin enhanced dabrafenib‐mediated inhibition of cell proliferation, migration and invasion, and promoted dabrafenib‐induced apoptosis and cell cycle arrest in anaplastic thyroid cancer cells. Molecular mechanistic studies further uncovered that melatonin synergized with dabrafenib to inhibit AKT and EMT signalling pathways. Furthermore, melatonin and dabrafenib synergistically inhibited the expression of hTERT, and the inhibition of cell viability and the induction of cell cycle arrest mediated by the combination of these two drugs were reversed by hTERT overexpression. Taken together, our results demonstrated that melatonin synergized the anti‐tumour effect of dabrafenib in human anaplastic thyroid cancer cells by inhibiting multiple signalling pathways, and provided new insights in exploring the potential therapeutic targets for the treatment of anaplastic thyroid cancer.

中文翻译：

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褪黑素通过抑制AKT / hTERT信号转导，协同BRAF靶向剂dabrafenib治疗间变性甲状腺癌。

作为BRAF激酶的选择性抑制剂，dabrafenib对BRAFV600E突变型间变性甲状腺癌患者显示出有效的抗肿瘤活性。但是，甲状腺癌细胞对达拉非尼的耐药性限制了其治疗效果。检验了褪黑素和达布拉非尼单药治疗或联合治疗对变性甲状腺癌癌细胞增殖，细胞周期阻滞，凋亡，迁移和侵袭的影响。还揭示了药物组合中涉及的分子机制。褪黑素增强了dabrafenib介导的对细胞增殖，迁移和侵袭的抑制，并促进了dabrafenib诱导的间变性甲状腺癌细胞凋亡和细胞周期停滞。分子机理研究进一步发现褪黑素与达拉非尼协同抑制AKT和EMT信号通路。此外，褪黑素和达布拉非尼协同抑制hTERT的表达，并且hTERT的过表达逆转了由这两种药物联合介导的细胞活力的抑制和细胞周期阻滞的诱导。综上所述，我们的结果表明褪黑素通过抑制多种信号通路，协同达拉非尼在人间变性甲状腺癌细胞中的抗肿瘤作用，并为探索治疗间变性甲状腺癌的潜在治疗靶点提供了新见识。