PRMT5 inhibition disrupts splicing and stemness in glioblastoma
Patty Sachamitr, Jolene Caifeng Ho, Felipe E. Ciamponi, Wail Ba-Alawi, Fiona J. Coutinho, Paul Guilhamon, Michelle Kushida, Florence M.G. Cavalli, Lilian Lee, Naghmeh Rastegar, Victoria Vu, María Sánchez‐Osuna, Jasmin Coulombe‐Huntington, Evgeny Kanshin, Heather Whetstone, Mathieu Durand, P Thibault, Kirsten Hart, Maria Mangos, Joseph Veyhl, Wenjun Chen, Nhat Tran, Bang-Chi Duong, Ahmed Aman, Xinghui Che, Xiaoyang Lan, Owen Whitley, Olga Zaslaver, Dalia Baršytė-Lovejoy, Laura M. Richards, Ian J. Restall, Amy A. Caudy, Hannes Röst, Zahid 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, C.H. Arrowsmith, Peter B. Dirks
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.