BMS-794833 reduces anlotinib resistance in osteosarcoma by targeting the VEGFR/Ras/CDK2 pathway

Qingtao Meng; Jian Han; Peng Wang; Chenxu Jia; Mingyang Guan; Bolun Zhang; Wenzhi Zhao

doi:10.1016/j.jbo.2024.100594

BMS-794833 reduces anlotinib resistance in osteosarcoma by targeting the VEGFR/Ras/CDK2 pathway

J Bone Oncol. 2024 Mar 16:45:100594. doi: 10.1016/j.jbo.2024.100594. eCollection 2024 Apr.

Authors

Qingtao Meng^{1

2}, Jian Han², Peng Wang³, Chenxu Jia², Mingyang Guan², Bolun Zhang², Wenzhi Zhao¹

Affiliations

¹ Department of Orthopedics, The Second Affiliated Hospital of Dalian Medical University, Dalian 116028, China.
² Department of Orthopedics, Dalian NO.3 People's Hospital, Dalian 116091, China.
³ Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, China.

Abstract

Background: 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.

Methods: 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.

Results: 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 in vivo.

Conclusion: 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.

Keywords: Anlotinib; CDK2; Osteosarcoma; Synergy effect; VEGFR.