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Abemaciclib is synergistic with doxorubicin in osteosarcoma pre-clinical models via inhibition of CDK4/6–Cyclin D–Rb pathway

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Abstract

Background

Osteosarcoma is a prevalent type of bone tumor in children and adolescents, with limited treatment and poor prognosis. Abemaciclib, an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), is approved for the treatment of advanced breast cancer as single agent therapy and is currently under investigation in clinical trials for the treatment of several solid tumors.

Methods

The efficacy of abemaciclib was determined using osteosarcoma cellular assays and xenograft mouse model. The combination studies were performed based on the Chou-Talalay method. Immunoblotting analysis was performed to determine the underlying mechanisms of abemaciclib in osteosarcoma cell lines.

Results

Abemaciclib potently inhibits growth, anchorage-independent colony formation and survival of a panel of osteosarcoma cell lines, with IC50 range from 90 nM to >20 μM. In addition, the combination of abemaciclib and doxorubicin is synergistic and antagonistic in abemaciclib-sensitive (IC50 <1 μM) and abemaciclib-resistant (IC50 >1 μM), respectively. Abemaciclib inhibits tumor formation and growth in a dose-dependent manner without causing significant drug toxicity in mice. The combination of abemaciclib and doxorubicin results in much greater efficacy than doxorubicin alone in inhibiting tumor growth throughout the whole treatment duration. Abemaciclib acts on osteosarcoma via suppressing CDK4/6-Cyclin D-Rb pathway.

Conclusions

Our pre-clinical evidence provides a rationale of initializing clinical trial of investigating the efficacy of abemaciclib in combination with doxorubicin in osteosarcoma patients. Our work also highlights the therapeutic value of CDK4/6 inhibition in osteosarcoma with proper function of Rb.

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Data availability

Data will be made available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by a research grant provided by Hubei University of Medicine (20170616).

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Authors and Affiliations

  1. Department of Rehabilitation Medicine, Renmin Hospital, Hubei University of Medicine, Maojian District, Chaoyangzhong Road 39, Shiyan, 442000, China

    Deli Wang & Haiqin Bao

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  1. Deli Wang
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Correspondence to Haiqin Bao.

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Wang, D., Bao, H. Abemaciclib is synergistic with doxorubicin in osteosarcoma pre-clinical models via inhibition of CDK4/6–Cyclin D–Rb pathway. Cancer Chemother Pharmacol 89, 31–40 (2022). https://doi.org/10.1007/s00280-021-04363-6

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