Tocilizumab (monoclonal anti-IL-6R antibody) reverses anlotinib resistance in osteosarcoma
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Updated: Jul 24, 2025
Intratibial Osteosarcoma Cell Injection to Generate Orthotopic Osteosarcoma and Lung Metastasis Mouse Models
Published on: October 28, 2021
Jiuhui Xu1,2, Chenglong Chen2,3, Kunkun Sun4
1Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, China.
Purpose:
Anlotinib, a tyrosine kinase inhibitor (TKI) has been in clinical application to inhibit malignant cell growth and lung metastasis in osteosarcoma (OS). However, a variety of drug resistance phenomena have been observed in the treatment. We aim to explore the new target to reverse anlotinib resistance in OS.
Materials And Methods:
In this study, we established four OS anlotinib-resistant cell lines, and RNA-sequence was performed to evaluate differentially expressed genes. We verified the results of RNA-sequence by PCR, western blot and ELISA assay. We further explored the effects of tocilizumab (anti- IL-6 receptor), either alone or in combined with anlotinib, on the inhibition of anlotinib-resistant OS cells malignant viability by CCK8, EDU, colony formation, apoptosis, transwell, wound healing, Cytoskeletal stain assays, and xenograft nude mouse model. The expression of IL-6 in 104 osteosarcoma samples was tested by IHC.
Results:
We found IL-6 and its downstream pathway STAT3 were activated in anlotinib-resistant osteosarcoma. Tocilizumab impaired the tumor progression of anlotinib-resistant OS cells, and combined treatment with anlotinib augmented these effects by inhibiting STAT3 expressions. IL-6 was highly expressed in patients with OS and correlated with poor prognosis.
Conclusion:
Tocilizumab could reverse anlotinib resistance in OS by IL-6/STAT3 pathway and the combination treatment with anlotinib rationalized further studies and clinical treatment of OS.
Insights
Tocilizumab reverses anlotinib resistance in osteosarcoma (OS) by targeting the IL-6/STAT3 pathway. Combining tocilizumab with anlotinib shows promise for treating resistant OS, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Anlotinib, a tyrosine kinase inhibitor (TKI), is used to treat osteosarcoma (OS) but drug resistance is a significant challenge.
- Understanding the mechanisms of anlotinib resistance is crucial for developing effective treatment strategies.
Purpose of the Study:
- To identify novel targets for reversing anlotinib resistance in osteosarcoma.
- To investigate the role of the IL-6/STAT3 pathway in anlotinib-resistant OS.
Main Methods:
- Established anlotinib-resistant OS cell lines and utilized RNA sequencing to identify differentially expressed genes.
- Validated findings using PCR, Western blot, and ELISA.
- Assessed the efficacy of tocilizumab (anti-IL-6 receptor) alone and in combination with anlotinib in vitro and in a xenograft mouse model.
- Analyzed IL-6 expression in patient samples via immunohistochemistry.
Main Results:
- IL-6 and its downstream STAT3 pathway were found to be activated in anlotinib-resistant OS.
- Tocilizumab treatment inhibited tumor progression in resistant OS cells, with combined therapy enhancing these effects via STAT3 inhibition.
- High IL-6 expression in OS patients correlated with poor prognosis.
Conclusions:
- Tocilizumab can overcome anlotinib resistance in OS by modulating the IL-6/STAT3 pathway.
- Combination therapy with anlotinib and tocilizumab warrants further investigation for clinical application in OS treatment.
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