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

Qingtao Meng^1,2, Jian Han², Peng Wang³

¹Department of Orthopedics, The Second Affiliated Hospital of Dalian Medical University, Dalian 116028, China.

Journal of Bone Oncology

|March 27, 2024

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.

Insights

This study shows BMS-794833 can overcome anlotinib resistance in osteosarcoma by targeting the VEGFR/Ras/CDK2 pathway. Combining BMS-794833 with anlotinib offers a synergistic treatment for osteosarcoma.

Area of Science:

Oncology
Pharmacology
Molecular Biology

Background:

Osteosarcoma is a highly malignant bone tumor with poor prognosis.
Anlotinib, a multi-target tyrosine kinase inhibitor (TKI), is a first-line treatment for advanced osteosarcoma.
Drug resistance to anlotinib is a significant clinical challenge, necessitating novel therapeutic strategies.

Purpose of the Study:

To investigate the potential of BMS-794833 in overcoming anlotinib resistance in osteosarcoma.
To elucidate the molecular mechanisms underlying BMS-794833's effect on anlotinib resistance.
To evaluate the synergistic therapeutic potential of combining BMS-794833 and anlotinib in osteosarcoma treatment.

Main Methods:

Cell Counting Kit-8 (CCK8) assays were used to assess drug sensitivity.
Bioinformatics analysis and rescue experiments identified key signaling pathways.
In vivo studies utilized a cell line-based xenograft model to evaluate therapeutic efficacy.

Main Results:

BMS-794833 significantly sensitized osteosarcoma cells to anlotinib.
The observed sensitization was dependent on the VEGFR/Ras/CDK2 pathway.
Combined treatment with BMS-794833 and anlotinib demonstrated synergistic therapeutic effects in vivo.

Conclusions:

BMS-794833 effectively reduces anlotinib resistance in osteosarcoma by targeting the VEGFR/Ras/CDK2 pathway.
This study provides a theoretical basis for using VEGFR-targeting drugs in combination with anlotinib to overcome drug resistance in osteosarcoma.

Read full analysis

Keywords:

Anlotinib CDK2 Osteosarcoma Synergy effect VEGFR

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