ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Pharmacology of Anti-Cancer Drugs
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1671798
RET Inhibitor Pralsetinib Suppresses TMZ-resistant Glioma Growth via Regulating of Spermine Production
Provisionally accepted
Lingyun Ma1
Hang Gong2Wei Sun3Jialing Deng2Qinghua Zhang2Jianzhao Niu1Huimin Sun1Xue Han4
Nina Xue2
Ming Ji4
Qian Liu1*- 1National Institutes for Food and Drug Control, Beijing, China
- 2Chinese Academy of Medical Sciences and Peking Union Medical College Institute of Materia Medica, Beijing, China
- 3Ningguo City People’s Hospital, Ningguo, China
- 4National Engineering Research Center for the Development of New Drugs, Beijing, China
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Glioma is the most common malignant tumor of the central nervous system and is characterized by altered cellular metabolism. Although temozolomide (TMZ)-based adjuvant treatment has improved overall patient survival, clinical outcomes remain unsatisfactory. TMZ resistance is a major contributing factor. The mechanisms underlying TMZ resistance are highly complex. In this study, we found that spermine synthase (SMS) was highly expressed in gliomas that showed a poor clinical response to TMZ treatment. Spermine, the metabolic product of SMS, was also elevated in TMZ-resistant glioma cells and promoted their proliferation. Further investigation revealed that pralsetinib, a selective RET inhibitor, exhibited significant antitumor activity against TMZ-resistant glioma cells both in vitro and in vivo. Mechanistically, pralsetinib inhibited the spermine-induced activation of the PI3K/AKT pathway and downregulated SMS expression, leading to reduced spermine production. Our findings suggest a potential new pharmacological application for pralsetinib in the treatment of TMZ-resistant glioma.
Keywords: Glioma, TMZ resistance, Spermine, Spermine Synthase, Pralsetinib
Received: 23 Jul 2025; Accepted: 24 Sep 2025.
Copyright: © 2025 Ma, Gong, Sun, Deng, Zhang, Niu, Sun, Han, Xue, Ji and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Qian Liu, liuqian@nifdc.org.cn
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