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Dual PRMT5 and MAT2A Inhibition Kills MTAP-Deficient Gliomas
- Researchers have developed a dual inhibition strategy targeting PRMT5 and MAT2A enzymes in MTAP homozygous-deficient gliomas, offering a promising therapeutic approach for aggressive brain tumors resistant to standard treatments.
- MTAP deletion in gliomas leads to metabolic adaptations, making cells susceptible to alterations in methionine metabolism and methylation dynamics through PRMT5 and MAT2A inhibition.
- Synthetic lethality achieved by targeting both enzymes simultaneously results in significant glioma cell viability impairment, affecting RNA splicing fidelity, epigenetic reprogramming, and the global methylome.
- Dual enzymatic targeting induces metabolic and epigenetic catastrophes in MTAP-null cells, leading to apoptosis and halting tumor progression more effectively than single-agent interventions.
- The study underscores PRMT5 and MAT2A as actionable drug targets, offering a beacon of hope for MTAP-deficient glioma patients with limited therapeutic options and unfavorable prognoses.
- Experimental validations in glioma models demonstrate tumor growth retardation, reduced proliferation, and increased apoptosis following combined PRMT5 and MAT2A inhibition.
- The research extends beyond gliomas, suggesting applicability of synthetic lethality in other MTAP-deficient cancers like pancreatic and lung malignancies with similar genomic deletions.
- In-depth mechanistic insights reveal how combined inhibition disrupts critical cellular pathways, inducing RNA splicing defects, epigenetic alterations, and shifts in gene regulation towards apoptosis.
- The potential to bypass the blood-brain barrier challenge in glioma therapeutics is highlighted, with promising brain penetration profiles of PRMT5 and MAT2A inhibitors enhancing clinical feasibility.
- Precision targeting of MTAP-deleted gliomas minimizes collateral toxicity on normal tissues, reducing adverse effects and enabling combinatorial regimens with standard therapies like temozolomide or radiotherapy.
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