The RET inhibitor pralsetinib suppresses TMZ-resistant glioma growth by regulating spermine production
Lingyun Ma1, Hang Gong2, Wei Sun3
1NMPA Key Laboratory for Quality Research and Evaluation of Chemical Drugs, National Institutes for Food and Drug Control, Beijing, China.
Objective:
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. This study aimed to elucidate the role of spermine in TMZ resistance and to assess the antitumor activity of kinase inhibitors against TMZ-resistant glioma.
Methods:
The TCGA data from glioma patients treated with TMZ was analyzed and metabolomic analysis of both TMZ-sensitive and TMZ-resistant glioma cells was performed. A series of compounds in both TMZ-sensitive and TMZ-resistant glioma cells were screened, and their brain penetration capacity was tested by MacroFlux assay. The antitumor activity of pralsetinib was evaluated in vitro and in vivo.
Results:
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.
Conclusion:
Our findings reveal the role of spermine in TMZ-resistant glioma and suggest a potential new pharmacological application for pralsetinib in the glioma treatment.
Insights
Spermine promotes glioma cell growth and resistance to temozolomide (TMZ). The drug pralsetinib effectively inhibits this resistance by targeting the spermine pathway, offering a new treatment strategy for glioma.
Area of Science:
- Neuro-oncology
- Cancer Metabolism
- Drug Resistance
Background:
- Glioma is a common brain tumor with limited treatment options.
- Temozolomide (TMZ) resistance significantly impacts patient outcomes.
- Altered cellular metabolism is a hallmark of glioma.
Purpose of the Study:
- Investigate the role of spermine in TMZ resistance in glioma.
- Evaluate the efficacy of kinase inhibitors against TMZ-resistant glioma.
Main Methods:
- Analyzed TCGA data and performed metabolomic analysis of glioma cells.
- Screened compounds for antitumor activity and brain penetration.
- Assessed pralsetinib's efficacy in vitro and in vivo.
Main Results:
- Spermine synthase (SMS) and spermine levels were elevated in TMZ-resistant gliomas.
- Pralsetinib demonstrated significant antitumor activity against TMZ-resistant glioma cells.
- Pralsetinib inhibited the PI3K/AKT pathway and reduced spermine production.
Conclusions:
- Spermine plays a crucial role in TMZ resistance in glioma.
- Pralsetinib shows promise as a therapeutic agent for TMZ-resistant glioma.
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