PRMT5 inhibition disrupts splicing and stemness in glioblastoma

Patty Sachamitr, Jolene C. Ho, Felipe E. Ciamponi, Wail Ba-Alawi, Fiona J. Coutinho, Paul Guilhamon, Michelle M. Kushida, Florence M. G. Cavalli, Lilian Lee, Naghmeh Rastegar, Victoria Vu, María Sánchez-Osuna, Jasmin Coulombe-Huntington, Evgeny Kanshin, Heather Whetstone, Mathieu Durand, Philippe Thibault, Kirsten Hart, Maria Mangos, Joseph Veyhl, Wenjun Chen, Nhat Tran, Bang-Chi Duong, Ahmed M. Aman, Xinghui Che, Xiaoyang Lan, Owen Whitley, Olga Zaslaver, Dalia Barsyte-Lovejoy, Laura M. Richards, Ian Restall, Amy Caudy, Hannes L. Röst, Zahid Quyoom Bonday, Mark Bernstein, Sunit Das, Michael D. Cusimano, Julian Spears, Gary D. Bader, Trevor J. Pugh, Mike Tyers, Mathieu Lupien, Benjamin Haibe-Kains, H. Artee Luchman, Samuel Weiss, Katlin B. Massirer, Panagiotis Prinos (), Cheryl H. Arrowsmith () and Peter B. Dirks ()
Additional contact information
Patty Sachamitr: The Hospital for Sick Children
Jolene C. Ho: University of Toronto
Felipe E. Ciamponi: University of Campinas (UNICAMP)
Wail Ba-Alawi: University Health Network
Fiona J. Coutinho: The Hospital for Sick Children
Paul Guilhamon: The Hospital for Sick Children
Michelle M. Kushida: The Hospital for Sick Children
Florence M. G. Cavalli: The Hospital for Sick Children
Lilian Lee: The Hospital for Sick Children
Naghmeh Rastegar: The Hospital for Sick Children
Victoria Vu: University of Toronto
María Sánchez-Osuna: Université de Montréal
Jasmin Coulombe-Huntington: Université de Montréal
Evgeny Kanshin: Université de Montréal
Heather Whetstone: The Hospital for Sick Children
Mathieu Durand: Université de Sherbrooke
Philippe Thibault: Université de Sherbrooke
Kirsten Hart: University of Toronto
Maria Mangos: University of Toronto
Joseph Veyhl: University of Toronto
Wenjun Chen: University of Toronto
Nhat Tran: University of Toronto
Bang-Chi Duong: University of Toronto
Ahmed M. Aman: Ontario Institute for Cancer Research
Xinghui Che: The Hospital for Sick Children
Xiaoyang Lan: The Hospital for Sick Children
Owen Whitley: University of Toronto
Olga Zaslaver: University of Toronto
Dalia Barsyte-Lovejoy: University of Toronto
Laura M. Richards: University Health Network
Ian Restall: University of Calgary
Amy Caudy: University of Toronto
Hannes L. Röst: University of Toronto
Zahid Quyoom Bonday: Eli Lilly and Company
Mark Bernstein: University of Toronto
Sunit Das: University of Toronto
Michael D. Cusimano: St. Michael’s Hospital
Julian Spears: University of Toronto
Gary D. Bader: University of Toronto
Trevor J. Pugh: University Health Network
Mike Tyers: Université de Montréal
Mathieu Lupien: University Health Network
Benjamin Haibe-Kains: University Health Network
H. Artee Luchman: University of Calgary
Samuel Weiss: University of Calgary
Katlin B. Massirer: University of Campinas (UNICAMP)
Panagiotis Prinos: University of Toronto
Cheryl H. Arrowsmith: University of Toronto
Peter B. Dirks: The Hospital for Sick Children

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21204-5

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