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Disruption of splicing, proliferation and stemness via PRMT5 inhibition as a therapeutic strategy for GBM

ABSTRACT: 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 caused 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.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Eric Bonneil

LAB HEAD: Mike Tyers

PROVIDER: PXD021635 | Pride | 2020-11-03

REPOSITORIES: pride

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			Action	DRS
	PRMT5_G561_GSK591_R1.raw	Raw
	PRMT5_G561_GSK591_R2.raw	Raw
	PRMT5_G561_GSK591_R3.raw	Raw
	PRMT5_G561_LLY283_R1.raw	Raw
	PRMT5_G561_LLY283_R2.raw	Raw

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