Developmental and Stem Cell Biology Program and Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada.
Nat Commun. 2021 Feb 12;12(1):979. doi: 10.1038/s41467-021-21204-5.
Glioblastoma (GBM) is a deadly cancer in which cancer stem cells (CSCs) sustain tumor growth and contribute to therapeutic resistance. Protein arginine methyltransferase 5 (PRMT5) has recently emerged as a promising target in GBM. Using two orthogonal-acting inhibitors of PRMT5 (GSK591 or LLY-283), we show that pharmacological inhibition of PRMT5 suppresses the growth of a cohort of 46 patient-derived GBM stem cell cultures, with the proneural subtype showing greater sensitivity. We show that PRMT5 inhibition causes widespread disruption of splicing across the transcriptome, particularly affecting cell cycle gene products. We identify a GBM splicing signature that correlates with the degree of response to PRMT5 inhibition. Importantly, we demonstrate that LLY-283 is brain-penetrant and significantly prolongs the survival of mice with orthotopic patient-derived xenografts. Collectively, our findings provide a rationale for the clinical development of brain penetrant PRMT5 inhibitors as treatment for GBM.
胶质母细胞瘤（GBM）是一种致命的癌症，其中癌症干细胞（CSCs）维持肿瘤生长并导致治疗耐药性。蛋白精氨酸甲基转移酶 5（PRMT5）最近成为 GBM 的一个有前途的靶点。使用两种正交作用的 PRMT5 抑制剂（GSK591 或 LLY-283），我们表明 PRMT5 的药理抑制抑制了 46 例患者来源的 GBM 干细胞培养物的生长，其中神经前体细胞亚型表现出更高的敏感性。我们表明 PRMT5 抑制会导致整个转录组剪接的广泛破坏，特别是影响细胞周期基因产物。我们确定了一个与 PRMT5 抑制反应程度相关的 GBM 剪接特征。重要的是，我们证明了 LLY-283 具有脑穿透性，并显著延长了荷瘤患者来源异种移植小鼠的存活时间。总之，我们的研究结果为开发脑穿透性 PRMT5 抑制剂作为 GBM 治疗提供了依据。
