Osteosarcoma, a tumor that originates from bone cells, has a poor prognosis and a high degree of malignancy. Anlotinib, a small-molecule multi-target tyrosine kinase inhibitor (TKI), is the first-line drug in treating osteosarcoma, especially in late-stage osteosarcoma. However, patients often develop resistance after using anlotinib for a certain period, which poses a challenge to its further clinical application. Recently, several TKIs, for instance regorafenib and cabozantinib, have showed clinical interest in treating osteosarcoma and target both vascular endothelial growth factor receptor (VEGFR) and mesenchymal epithelial transition factor (c-MET). Therefore, the identification of new TKI warrants further investigation. We performed CCK8 aasays to confirm that BMS-794833 sensitization osteosarcoma cells to anlotinib. Bioinformatics analysis and rescue experiments showed that the reduce of resistance were dependent on the VEGFR/Ras/CDK2 pathway. Cell line based xenograft model were used to demonstrate that BMS-794833 and anlotinib could synergistically treat OS. Here, we found that BMS-794833 reduced anlotinib resistance in osteosarcoma by targeting the VEGFR/Ras/CDK2 pathway. CCK8 assay showed that BMS-794833 significantly improved the resistance of osteosarcoma cells to anlotinib. The results of rescue experiments showed that the regulatory effects of BMS-794833 on the proliferation and drug resistance of osteosarcoma cells were dependent on the VEGFR/Ras/CDK2 pathway. In addition, BMS-794833 affected the resistance of osteosarcoma cells to anlotinib through epithelial–mesenchymal transition (EMT) and apoptosis pathways. More importantly, BMS-794833 and anlotinib exerted synergistic therapeutic effects against osteosarcoma . Altogether, this study reveals a new (VEGFR)-targeting drug that can be combined with anlotinib for the treatment of osteosarcoma, which provides an important theoretical basis for overcoming anlotinib resistance.

中文翻译：

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BMS-794833 通过靶向 VEGFR/Ras/CDK2 通路降低骨肉瘤中的安罗替尼耐药性

骨肉瘤是一种起源于骨细胞的肿瘤，预后较差，恶性程度较高。安罗替尼是一种小分子多靶点酪氨酸激酶抑制剂（TKI），是治疗骨肉瘤尤其是晚期骨肉瘤的一线药物。然而，患者在使用安罗替尼一段时间后往往会产生耐药性，这对其进一步的临床应用提出了挑战。最近，几种 TKI，例如瑞格非尼和卡博替尼，在治疗骨肉瘤方面表现出临床兴趣，并靶向血管内皮生长因子受体 (VEGFR) 和间充质上皮转化因子 (c-MET)。因此，新 TKI 的鉴定值得进一步研究。我们进行了 CCK8 分析，以确认 BMS-794833 使骨肉瘤细胞对安罗替尼敏感。生物信息学分析和挽救实验表明，耐药性的降低依赖于VEGFR/Ras/CDK2通路。基于细胞系的异种移植模型被用来证明 BMS-794833 和安罗替尼可以协同治疗 OS。在这里，我们发现 BMS-794833 通过靶向 VEGFR/Ras/CDK2 通路降低骨肉瘤中的安罗替尼耐药性。 CCK8检测显示BMS-794833显着提高骨肉瘤细胞对安罗替尼的耐药性。拯救实验结果表明，BMS-794833对骨肉瘤细胞增殖和耐药的调节作用依赖于VEGFR/Ras/CDK2通路。此外，BMS-794833通过上皮间质转化（EMT）和细胞凋亡途径影响骨肉瘤细胞对安罗替尼的耐药性。更重要的是，BMS-794833和安罗替尼对骨肉瘤发挥协同治疗作用。总而言之，该研究揭示了一种可与安罗替尼联合治疗骨肉瘤的新型（VEGFR）靶向药物，为克服安罗替尼耐药性提供了重要的理论基础。