Kinome-wide CRISPR-Cas9 knockout screens revealed PLK1 as a therapeutic target for osteosarcoma.

Autor: Wang R; Laboratory of Bone Tissue Engineering, Beijing Laboratory of Biomedical Materials, National Center for Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China., Wang D; State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China., Bai X; Cranio-Maxillo-Facial Surgery Department, Plastic Surgery Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China., Guo J; Laboratory of Bone Tissue Engineering, Beijing Laboratory of Biomedical Materials, National Center for Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China., Xia S; Cranio-Maxillo-Facial Surgery Department, Plastic Surgery Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China., Cheng Y; Laboratory of Bone Tissue Engineering, Beijing Laboratory of Biomedical Materials, National Center for Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China., Gu Y; State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China., Wang Q; Laboratory of Bone Tissue Engineering, Beijing Laboratory of Biomedical Materials, National Center for Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China., Nie J; Laboratory of Bone Tissue Engineering, Beijing Laboratory of Biomedical Materials, National Center for Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China., Chen D; Laboratory of Bone Tissue Engineering, Beijing Laboratory of Biomedical Materials, National Center for Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China. chendafujst@126.com., Liu W; Department of Orthopaedic Oncology Surgery, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China. liuweifengjst@126.com., Liang J; State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China. liangjunbo@ibms.pumc.edu.cn.
Jazyk: angličtina
Zdroj: Cell death discovery [Cell Death Discov] 2023 Jul 07; Vol. 9 (1), pp. 231. Date of Electronic Publication: 2023 Jul 07.
DOI: 10.1038/s41420-023-01526-7
Abstrakt: Osteosarcoma is the most common malignant bone tumor, tending to be aggressive and recurrent. The therapeutic development for treating osteosarcoma has been largely hampered by the lack of effective and specific targets. Using kinome-wide CRISPR-Cas9 knockout screens, we systematically revealed a cohort of kinases essential for the survival and growth of human osteosarcoma cells, in which Polo-like kinase 1 (PLK1) appeared as a specific prominent hit. PLK1 knockout substantially inhibited proliferation of osteosarcoma cells in vitro and the tumor growth of osteosarcoma xenograft in vivo. Volasertib, a potent experimental PLK1 inhibitor, can effectively inhibit the growth of the osteosarcoma cell lines in vitro. It can also disrupt the development of tumors in the patient-derived xenograft (PDX) models in vivo. Furthermore, we confirmed that the mode of action (MoA) of volasertib is primarily mediated by the cell-cycle arrest and apoptosis triggered by DNA damage. As PLK1 inhibitors are entering phase III clinical trials, our findings provide important insights into the efficacy and MoA of the relevant therapeutic approach for combating osteosarcoma.
(© 2023. The Author(s).)
Databáze: MEDLINE
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