Abstract：
OBJECTIVE: This study aimed to investigate BVD-523 (ulixertinib), an adenosine triphosphate (ATP)-dependent extracellular signal-regulated kinases 1/2 inhibitor, for its antitumor potential in thyroid cancer.
METHODS: Ten thyroid cancer cell lines known to carry mitogen-activated protein kinase (MAPK)-activated mutations, including v-Raf murine sarcoma viral oncogene homolog B (BRAF) and rat sarcoma virus (RAS) mutations, were examined. Cells were exposed to a 10-fold concentration gradient ranging from 0 to 3000 nM for 5 days. The half-inhibitory concentration was determined using the Cell Counting Kit-8 assay. Following BVD-523 treatment, cell cycle analysis was conducted using flow cytometry. In addition, the impact of BVD-523 on extracellular signal-regulated kinase (ERK)- dependent ribosomal S6 kinase (RSK) activation and the expression of cell cycle markers were assessed through western blot analysis.
RESULTS: BVD-523 significantly inhibited thyroid cancer cell proliferation and induced G1/S cell cycle arrest dose-dependently. Notably, cell lines carrying MAPK mutations, especially those with the BRAF V600E mutation, exhibited heightened sensitivity to BVD-523\'s antitumor effects. Furthermore, BVD-523 suppressed cyclin D1 and phosphorylated retinoblastoma protein expression, and it robustly increased p27 levels in an RSK-independent manner.
CONCLUSIONS: This study reveals the potent antitumor activity of BVD-523 against thyroid cancer cells bearing MAPK-activating mutations, offering promise for treating aggressive forms of thyroid cancer.
METHODS: Ten thyroid cancer cell lines known to carry mitogen-activated protein kinase (MAPK)-activated mutations, including v-Raf murine sarcoma viral oncogene homolog B (BRAF) and rat sarcoma virus (RAS) mutations, were examined. Cells were exposed to a 10-fold concentration gradient ranging from 0 to 3000 nM for 5 days. The half-inhibitory concentration was determined using the Cell Counting Kit-8 assay. Following BVD-523 treatment, cell cycle analysis was conducted using flow cytometry. In addition, the impact of BVD-523 on extracellular signal-regulated kinase (ERK)- dependent ribosomal S6 kinase (RSK) activation and the expression of cell cycle markers were assessed through western blot analysis.
RESULTS: BVD-523 significantly inhibited thyroid cancer cell proliferation and induced G1/S cell cycle arrest dose-dependently. Notably, cell lines carrying MAPK mutations, especially those with the BRAF V600E mutation, exhibited heightened sensitivity to BVD-523\'s antitumor effects. Furthermore, BVD-523 suppressed cyclin D1 and phosphorylated retinoblastoma protein expression, and it robustly increased p27 levels in an RSK-independent manner.
CONCLUSIONS: This study reveals the potent antitumor activity of BVD-523 against thyroid cancer cells bearing MAPK-activating mutations, offering promise for treating aggressive forms of thyroid cancer.
摘要：
目的：本研究旨在调查BVD-523（ulixertinib），三磷酸腺苷（ATP）依赖性细胞外信号调节激酶1/2抑制剂，它在甲状腺癌中的抗肿瘤潜力。
方法：10种已知携带丝裂原活化蛋白激酶（MAPK）活化突变的甲状腺癌细胞系，包括v-Raf鼠肉瘤病毒癌基因同源物B（BRAF）和大鼠肉瘤病毒（RAS）突变，进行了检查。将细胞暴露于0至3000nM的10倍浓度梯度5天。使用细胞计数试剂盒-8测定法测定半抑制浓度。BVD-523治疗后，使用流式细胞术进行细胞周期分析。此外,通过westernblot分析评估BVD-523对细胞外信号调节激酶(ERK)依赖性核糖体S6激酶(RSK)活化和细胞周期标志物表达的影响.
结果：BVD-523显著抑制甲状腺癌细胞增殖，并呈剂量依赖性诱导G1/S细胞周期阻滞。值得注意的是,携带MAPK突变的细胞系，尤其是那些有BRAFV600E突变的,对BVD-523的抗肿瘤作用表现出更高的敏感性。此外，BVD-523抑制细胞周期蛋白D1和磷酸化视网膜母细胞瘤蛋白表达，它以不依赖于RSK的方式强劲地增加了p27水平。
结论：这项研究揭示了BVD-523对携带MAPK激活突变的甲状腺癌细胞的有效抗肿瘤活性，为治疗侵袭性甲状腺癌提供了希望。
方法：10种已知携带丝裂原活化蛋白激酶（MAPK）活化突变的甲状腺癌细胞系，包括v-Raf鼠肉瘤病毒癌基因同源物B（BRAF）和大鼠肉瘤病毒（RAS）突变，进行了检查。将细胞暴露于0至3000nM的10倍浓度梯度5天。使用细胞计数试剂盒-8测定法测定半抑制浓度。BVD-523治疗后，使用流式细胞术进行细胞周期分析。此外,通过westernblot分析评估BVD-523对细胞外信号调节激酶(ERK)依赖性核糖体S6激酶(RSK)活化和细胞周期标志物表达的影响.
结果：BVD-523显著抑制甲状腺癌细胞增殖，并呈剂量依赖性诱导G1/S细胞周期阻滞。值得注意的是,携带MAPK突变的细胞系，尤其是那些有BRAFV600E突变的,对BVD-523的抗肿瘤作用表现出更高的敏感性。此外，BVD-523抑制细胞周期蛋白D1和磷酸化视网膜母细胞瘤蛋白表达，它以不依赖于RSK的方式强劲地增加了p27水平。
结论：这项研究揭示了BVD-523对携带MAPK激活突变的甲状腺癌细胞的有效抗肿瘤活性，为治疗侵袭性甲状腺癌提供了希望。
