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Chemical Probes Reveal Interferon-Driven Biomarkers of PRMT5 Inhibitor Sensitivity and Guide Synergistic Therapy in Triple-Negative Breast Cancer

ABSTRACT: This study employed 10x Genomics single-cell RNA sequencing (scRNA-seq) technology to investigate the effects of the combination of the PRMT5 inhibitor LLY283 and the PARP inhibitor Olaparib, as well as the triple combination with PD-1 blockade, on the tumor microenvironment in a mouse model of triple-negative breast cancer (TNBC). Our research uncovers the regulatory effects of these drugs and their combinations on the tumor microenvironment, providing new strategies and insights for future clinical therapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE292508 | GEO | 2025/03/20

REPOSITORIES: GEO

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PRMT5 inhibition by SCR-6920 leads to downregulation of HIF-1α and exhibits synergistic antitumor activity with bevacizumab in ovarian cancer

Project description:Protein arginine methyltransferase 5 (PRMT5) is a desirable anticancer target due to its extensive involvement in cellular processes associated with tumor initiation and progression. This study describes an oral PRMT5 selective inhibitor, SCR-6920, with potent inhibitory activity against multiple tumor types. Cryo-EM structure shows that SCR-6920 binds to PRMT5:MEP50 in a substrate-competitive mode with high binding affinity. Notably, RNAseq analysis links vascular endothelial growth factor (VEGF) to PRMT5 and further studies show that SCR-6920 downregulates hypoxia-inducible factor-1α (HIF-1α) expression through the ubiquitin-proteasome degradation pathway, thereby reducing downstream VEGF secretion. Further in vivo efficacy study demonstrates a synergistic effect for SCR-6920 combined with bevacizumab against ovarian cancer. Additionally, SCR-6920 improves the efficacy of clinical first-line ovarian cancer therapies (paclitaxel, docetaxel, doxorubicin, and olaparib). SCR-6920 has progressed into phase 1 clinical trials for solid tumors, and this study paves the way for its future clinical combination exploration in ovarian cancer.

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Chemical Probes Reveal Interferon-Driven Biomarkers of PRMT5 Inhibitor Sensitivity and Guide Synergistic Therapy in Triple-Negative Breast Cancer

Project description:Chemical Probes Reveal Interferon-Driven Biomarkers of PRMT5 Inhibitor Sensitivity and Guide Synergistic Therapy in Triple-Negative Breast Cancer

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Project description:Compared to intensely studied DNA methylation, protein methylation is less studied. PRMT5 is the major type II protein arginine methyltransferase catalyzing the symmetric dimethylation of arginine. Recent reports have indicated that PRMT5 is overexpressed in multiple cancer types, including prostate. However, the exact contribution of PRMT5 to prostate tumorigenesis is unknown. To explore PRMT5 in prostate cancer (PCa) therapeutically, we utilized a recently developed selective small molecule PRMT5 inhibitor (PRMT5i, EPZ015666) that has shown in vivo potency in MCL models. To understand the molecular mechanisms of action of PRMT5i in PCa, we performed deep RNA-seq analysis in PC3 and LNCaP cells treated with or without PRMT5i at 4 μM for 4 days in vitro.

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2024-01-05 | GSE230065 | GEO

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