2. Academic Validation
  3. PKMYT1 kinase ameliorates cisplatin sensitivity in osteosarcoma

PKMYT1 kinase ameliorates cisplatin sensitivity in osteosarcoma

  • Signal Transduct Target Ther. 2025 May 21;10(1):165. doi: 10.1038/s41392-025-02250-7.
Binfeng Liu # 1 2 3 4,  Wei Li # 2 5,  Wenchao Zhang 1 2 3,  Chengyao Feng 1 2 3,  Lu Wan 1 2 3,  Shasha He 6,  Ruiling Xu 1 2 3,  Zheng Fu 7,  Zhongyue Liu 2 3 8,  Haodong Xu 1 2 3,  Xin Jin 9 10,  Chao Tu 11 12 13 14,  Zhihong Li 15 16 17 18
Affiliations

Affiliations

  • 1 Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, China.
  • 2 National Clinical Research Center for Mental Disorders, and National Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China.
  • 3 Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital, Changsha, China.
  • 4 Hunan Engineering Research Center of AI Medical Equipment, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China.
  • 5 Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 6 Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
  • 7 Xinyi Biotech Co., Ltd, Lingang, Shanghai, 201306, PR China.
  • 8 Department of Neurosurgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
  • 9 National Clinical Research Center for Mental Disorders, and National Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China. jinxinxy2@csu.edu.cn.
  • 10 Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China. jinxinxy2@csu.edu.cn.
  • 11 Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, China. tuchao@csu.edu.cn.
  • 12 National Clinical Research Center for Mental Disorders, and National Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China. tuchao@csu.edu.cn.
  • 13 Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital, Changsha, China. tuchao@csu.edu.cn.
  • 14 Hunan Engineering Research Center of AI Medical Equipment, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China. tuchao@csu.edu.cn.
  • 15 Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, China. lizhihong@csu.edu.cn.
  • 16 National Clinical Research Center for Mental Disorders, and National Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China. lizhihong@csu.edu.cn.
  • 17 Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital, Changsha, China. lizhihong@csu.edu.cn.
  • 18 Hunan Engineering Research Center of AI Medical Equipment, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China. lizhihong@csu.edu.cn.
  • # Contributed equally.
PMID: 40393983 DOI: 10.1038/s41392-025-02250-7
Abstract

Cisplatin (DDP) remains a cornerstone therapy for osteosarcoma (OS); however, pervasive resistance severely limits its clinical efficacy and worsens patient outcomes. Developing strategies to enhance the chemotherapeutic responsiveness of OS cells is therefore of critical importance. Here, we conducted a kinome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screen, coupled with transcriptome Sequencing, to identify regulators of DDP sensitivity. This approach revealed protein kinase membrane-associated tyrosine/threonine 1 (PKMYT1) as a key regulator of DDP sensitivity in OS. Subsequent analysis of patient-derived clinical specimens, along with in vitro functional assays, demonstrated that DDP treatment induces the activation of PKMYT1 in OS cells. Importantly, PKMYT1 silencing markedly enhances cellular sensitivity to DDP, indicating its role in promoting chemoresistance. Mechanistically, PKMYT1 induces phosphorylation of nucleophosmin 1 (NPM1) at the S260 site, which competitively impairs NPM1 SUMOylation. This modification interferes with the recruitment of essential DNA damage response factors, including breast Cancer suppressor gene 1 (BRCA1), receptor-associated protein 80 (RAP80), and RADiation sensitive protein 51 (RAD51), ultimately affecting double-strand break (DSB) repair. Furthermore, the selective PKMYT1 Inhibitor RP6306 was found to synergize with DDP, amplifying its cytotoxic effects in OS cells. Collectively, these findings highlight PKMYT1 as a promising therapeutic target and provide a rationale for combinatorial strategies to overcome DDP resistance in OS.

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