pemrametostat (GSK3326595)

This study investigates the effects of two classes of PRMT5 inhibitors, GSK3326595 and TNG908, on breast cancer cell lines with different BRCA1/2 statuses to evaluate their therapeutic potential and synergy with PARP inhibitors. These findings highlight the potential of combining PRMT5 inhibitors with PARP inhibitors in a wide range of cancers beyond BRCA1/2 and MTAP mutants. Further investigation is warranted to elucidate the underlying mechanisms of sensitization and the timing of cellular responses to PRMT5 inhibition.

Notably, combination therapy using PRMT5 inhibitor GSK3326595 along with cisplatin and etoposide significantly delayed the recurrence of SCLC. Our findings reveal the promoting effect of post-chemotherapy inflammation on tumor recurrence from an epigenetic perspective and provide a potential therapeutic strategy for SCLC treatment.

Several small-molecule PRMT inhibitors, including GSK3326595 and EPZ015666, have entered early-phase clinical trials for solid tumors. This review examines the mechanistic basis and therapeutic rationale for targeting PRMTs in breast cancer and discusses combination approaches to overcome resistance. We integrate preclinical and emerging clinical data to highlight the potential antiangiogenic and tumor-suppressive effects of PRMT inhibitors, providing insights for future therapeutic strategies for breast cancer.

Importantly, combining the epigenetic anti-tumor drug GSK3326595 with CPT-11 significantly upregulates the immune receptor tyrosine-based inhibitory motif (TIGIT) level on CD8+ T cells and subsequently demonstrates impressive anti-tumor efficacy in vivo when additional anti-TIGIT is included. Collectively, this study reveals the crucial role of PRMT5 blockade combined with CPT-11 in inducing a mismatch repair deficiency-like state and provides a novel triple-drug combination therapy strategy as a potential treatment for patients with MSS CRC.

AS modulators such as PRMT5 inhibitor GSK3326595 enhance immunotherapy efficacy by upregulating MHC class II expression and promoting T cell infiltration, while RBM39 inhibitor indisulam induces tumor-specific neoantigens. Future efforts should focus on refining AS-targeting therapies, identifying predictive biomarkers, and integrating these approaches into clinical applications. This review highlights the therapeutic potential of AS modulation in cancer immunotherapy and its implications for advancing precision oncology.

Finally, we demonstrated that combining an anti-PD1 antibody with the PRMT5 inhibitor GSK3326595 markedly halts the progression of CRC. Our findings could serve as a basis for the development of a PRMT5-meR316-ALKBH5-CD276 axis-targeting treatment approach for CRC.

Collectively, our results provide a strong rationale and mechanistic insights for the clinical development of MRTX1719-based IO combinations in MTAP-loss tumors.

The safety profile was broadly consistent with other published PRMT5 inhibitor studies. ClinicalTrials.gov: NCT03614728.

Furthermore, treatment with the PRMT5 inhibitor pemrametostat and a selective ER degrader fulvestrant synergistically inhibits growth of ER+/RB-deficient cell-derived and patient-derived xenografts. These findings highlight dual ER and PRMT5 blockade as a potential therapeutic strategy to overcome resistance to CDK4/6i in ER+/RB-deficient breast cancer.

P1, N=288, Completed, GlaxoSmithKline | Active, not recruiting --> Completed

Methylation suppresses MST2 autophosphorylation and kinase activity by blocking its homodimerization, thereby inactivating Hippo signaling pathway in pancreatic cancer. Moreover, we also show that the specific PRMT5 inhibitor GSK3326595 re-activates the dysregulated Hippo signaling pathway and inhibits the growth of human pancreatic cancer xenografts in immunodeficient mice, thus suggesting potential clinical application of PRMT5 inhibitors in pancreatic cancer.

Combination MTDIA and AG-270 treatment differs from direct inhibition of PRMT5 by GSK3326595 by avoiding toxicity caused by cell death in the normal gut epithelium induced by the PRMT5 inhibitor. The combination of MTAP and MAT2a inhibitors expands this synthetic lethal approach to include MTAP cancers, especially the remaining 98% of CRCs without the MTAP genotype.