PRMT5 inhibition sensitizes glioblastoma tumor models to temozolomide
Background: Glioblastoma remains a challenging cancer to treat despite comprehensive multi-modal approaches involving maximal surgical resection, radiation, chemotherapy, and tumor-treating fields, leading to poor patient outcomes. Protein Arginine Methyltransferase 5 (PRMT5) is overexpressed in glioblastoma, and its inhibition has shown potential for anti-tumor effects. While Temozolomide (TMZ) is the standard chemotherapeutic agent for glioblastoma, tumor cells often develop resistance to TMZ over time. However, the role of PRMT5 in the development of resistance to glioblastoma therapies remains unclear.
Methods: We used patient-derived primary glioblastoma neurospheres (GBMNS) treated with the PRMT5 inhibitor LLY-283 or transfected with PRMT5-targeting siRNA. These cells were then exposed to TMZ and analyzed in vitro for functional and mechanistic effects. To assess in vivo efficacy, we employed an intracranial mouse xenograft model to evaluate the antitumor impact of combination therapy.
Results: Inhibition of PRMT5 enhanced the cytotoxic effect of TMZ and increased caspase 3/7 activity in GBMNS, suggesting that apoptosis is a key mechanism of cell death in the combination treatment. PRMT5 inhibition also counteracted TMZ-induced G2/M cell cycle arrest. Transcriptomic analysis revealed that PRMT5 inhibition reduces the expression of DNA damage repair genes. Notably, the combination therapy led to increased DNA double-strand breaks (indicated by H2AX foci) and enhanced DNA damage (as demonstrated by the comet assay), indicating that the treatment boosts TMZ-induced DNA damage. Specifically, LLY-283 treatment impaired homologous recombination repair in GBMNS. In vivo, the combination of LLY-283 and TMZ significantly reduced tumor growth and extended the survival of tumor-bearing mice.
Conclusion: The combination of LLY-283 and TMZ demonstrates significantly enhanced antitumor efficacy, suggesting that inhibiting PRMT5 alongside TMZ could offer a promising new therapeutic strategy for glioblastoma.