PRMT5 inhibition disrupts splicing and stemness in glioblastoma

Author(s):Show less -

Sachamitr, Patty ^{[1, 2, 3]} ; Ho, Jolene C. ^[1] ; Ciamponi, Felipe E. ^{[4, 5]} ; Ba-Alawi, Wail ^{[6, 7]} ; Coutinho, Fiona J. ^{[2, 3]} ; Guilhamon, Paul ^{[7, 2, 3]} ; Kushida, Michelle M. ^{[2, 3]} ; Cavalli, Florence M. G. ^{[2, 3]} ; Lee, Lilian ^{[2, 3]} ; Rastegar, Naghmeh ^{[2, 3]} ; Vu, Victoria ^{[1, 7]} ; Sanchez-Osuna, Maria ^[8] ; Coulombe-Huntington, Jasmin ^[8] ; Kanshin, Evgeny ^[8] ; Whetstone, Heather ^{[2, 3]} ; Durand, Mathieu ^[9] ; Thibault, Philippe ^[9] ; Hart, Kirsten ^{[6, 1]} ; Mangos, Maria ^[1] ; Veyhl, Joseph ^[1] ; Chen, Wenjun ^[1] ; Tran, Nhat ^[1] ; Duong, Bang-Chi ^[1] ; Aman, Ahmed M. ^[10] ; Che, Xinghui ^{[2, 3]} ; Lan, Xiaoyang ^{[2, 3]} ; Whitley, Owen ^{[11, 12]} ; Zaslaver, Olga ^{[11, 12]} ; Barsyte-Lovejoy, Dalia ^{[1, 13]} ; Richards, Laura M. ^{[6, 7]} ; Restall, Ian ^{[14, 15]} ; Caudy, Amy ^{[11, 12, 16]} ; Rost, Hannes L. ^{[11, 12]} ; Bonday, Zahid Quyoom ^[17] ; Bernstein, Mark ^{[18, 19]} ; Das, Sunit ^{[18, 20, 21]} ; Cusimano, Michael D. ^[21] ; Spears, Julian ^{[18, 22]} ; Bader, Gary D. ^{[11, 12]} ; Pugh, Trevor J. ^{[6, 7, 10]} ; Tyers, Mike ^[8] ; Lupien, Mathieu ^{[6, 7, 10]} ; Haibe-Kains, Benjamin ^{[6, 7, 23, 10, 24]} ; Luchman, H. Artee ^{[14, 15, 25]} ; Weiss, Samuel ^{[14, 15, 25]} ; Massirer, Katlin B. ^{[4, 5]} ; Prinos, Panagiotis ^[1] ; Arrowsmith, Cheryl H. ^{[6, 1, 7]} ; Dirks, Peter B. ^{[26, 11, 2, 3, 18, 20, 27]}

Affiliation:Show less -

^[1] Univ Toronto, Struct Genom Consortium, Toronto, ON - Canada

^[2] Hosp Sick Children, Dev & Stem Cell Biol Program, Toronto, ON - Canada

^[3] Hosp Sick Children, Arthur & Sonia Labatt Brain Tumor Res Ctr, Toronto, ON - Canada

^[4] Univ Campinas UNICAMP, Ctr Mol Biol & Genet Engn, Campinas - Brazil

^[5] Univ Campinas UNICAMP, Struct Genom Consortium, Campinas - Brazil

^[6] Univ Toronto, Dept Med Biophys, Toronto, ON - Canada

^[7] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON - Canada

^[8] Univ Montreal, Inst Res Immunol & Canc, Montreal, PQ - Canada

^[9] Univ Sherbrooke, RNom Platform, Sherbrooke, PQ - Canada

^[10] Ontario Inst Canc Res, Toronto, ON - Canada

^[11] Univ Toronto, Dept Mol Genet, Toronto, ON - Canada

^[12] Univ Toronto, Donnelly Ctr, Toronto, ON - Canada

^[13] Univ Toronto, Dept Pharmacol & Toxicol, Toronto, ON - Canada

^[14] Univ Calgary, Cumming Sch Med, Hotchkiss Brain Inst, Calgary, AB - Canada

^[15] Univ Calgary, Dept Cell Biol & Anat, Calgary, AB - Canada

^[16] Maple Flavored Solut LLC, Stony Brook, NY - USA

^[17] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 - USA

^[18] Univ Toronto, Dept Surg, Div Neurosurg, Toronto, ON - Canada

^[19] Univ Hlth Network, Toronto Western Hosp, Div Neurosurg, Toronto, ON - Canada

^[20] Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON - Canada

^[21] St Michaels Hosp, Div Neurosurg, Dept Surg, Toronto, ON - Canada

^[22] Univ Toronto, Dept Med Imaging, St Michaels Hosp, Toronto, ON - Canada

^[23] Univ Toronto, Dept Comp Sci, Toronto, ON - Canada

^[24] Vector Inst, Toronto, ON - Canada

^[25] Univ Calgary, Clark H Smith Brain Tumor Ctr, Cumming Sch Med, Calgary, AB - Canada

^[26] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON - Canada

^[27] Hosp Sick Children, Div Neurosurg, Toronto, ON - Canada

• Document type: Journal article
• Source: NATURE COMMUNICATIONS; v. 12, n. 1 FEB 12 2021.
• Web of Science Citations: 1

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 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. The arginine methyltransferase PRMT5 is over-expressed in cancer and has a role in the maintenance of stem cells. Here, the authors show that PRMT5 inhibitors can block the growth of patient derived glioblastoma stem cell cultures in vitro and in vivo, suggesting that PRMT5 inhibition may be a useful therapeutic strategy (AU)

• FAPESP's process: 16/25521-1 - Computational analysis of transcriptomic alterations induced by stress granules in human cells
• Grantee: Felipe Eduardo Ciamponi
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 15/25134-5 - Implementation of CLIP-seq computational analyzes for determination of target mRNAs and Caprin-1 protein binding sites
• Grantee: Felipe Eduardo Ciamponi
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 14/50897-0 - INCT 2014: Open-acess Medicinal Chemistry Centre (OpenMedChem)
• Grantee: Katlin Brauer Massirer
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 14/21704-9 - Impact of translational regulation into the neural differentiation
• Grantee: Mário Henrique Bengtson
• Support Opportunities: Research Grants - Young Investigators Grants