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Synergistic effect of adavosertib and fimepinostat on acute myeloid leukemia cells by enhancing the induction of DNA damage

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Summary

In recent years, a number of novel pharmaceutical agents have received approval for the management of acute myeloid leukemia (AML). However, there is still ample opportunity for enhancing efficacy. The Wee1 inhibitor adavosertib (ADA) shows promise for the treatment of AML. Based on the effect of drugs on DNA damage, we conducted a combination study involving ADA and fimepinostat (CUDC-907), a dual inhibitor of PI3K and histone deacetylase (HDAC). We observed that the combination of CUDC-907 and ADA exhibited a synergistic effect in enhancing the antileukemic activity in both AML cell lines and primary patient samples, demonstrating through flow cytometry analysis and MTT assay, respectively. Additionally, our study revealed that CUDC-907 has the ability to augment ADA-induced DNA damage, as determined by the measurement of γH2AX levels and the implementation of the alkaline comet assay. Through the utilization of western blotting analyses, targeted inhibitors, and ectopic overexpression, we propose that the downregulation of Wee1, CHK1, RNR, and c-Myc are the potential mechanisms. Our data support the development of ADA in combination with CUDC-907 for the treatment of AML.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Funding

National Natural Science Foundation of China,NSFC82100076,Projects of Jilin Province Science and Technology Development Plan,20220101284JC

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Author notes

  1. Yue Wang and Xingyu Lin these authors have contributed equally to this work.

Authors and Affiliations

  1. National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, School of Life Sciences, Jilin University, 2699 Qianjin Street, Changchun City, Jilin Province, China

    Yue Wang & Guan Wang

  2. Department of Thoracic Surgery, the First Hospital of Jilin University, Changchun, China

    Xingyu Lin

  3. Department of Pediatric Hematology, the First Hospital of Jilin University, 1 Xinmin Street, Changchun City, Jilin Province, China

    Yue Wang

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  1. Yue Wang
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Contributions

The study conception and design were from Guan Wang and Yue Wang (the First Hospital of Jilin University). Material preparation, data collection, and analysis were performed by Yue Wang (School of Life Sciences) and Xingyu Lin. The first draft of the manuscript was written by Guan Wang and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Yue Wang or Guan Wang.

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This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Human Ethics Committee of the First Hospital of Jilin University.

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Wang, Y., Lin, X., Wang, Y. et al. Synergistic effect of adavosertib and fimepinostat on acute myeloid leukemia cells by enhancing the induction of DNA damage. Invest New Drugs 42, 70–79 (2024). https://doi.org/10.1007/s10637-023-01415-x

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