Tatiana Erazo, Chiara M Evans, Daniel Zakheim, Karen L Chu, Alice Yunsi Refermat, Zahra Asgari, Xuejing Yang, Mariana Da Silva Ferreira, Sanjoy Mehta, Marco Vincenzo Russo, Andrea Knezevic, Xi-Ping Zhang, Zhengming Chen, Myles Fennell, Ralph Garippa, Venkatraman Seshan, Elisa de Stanchina, Olena Barbash, Connie Lee Batlevi, Christina S Leslie, Ari M Melnick, Anas Younes, Michael G Kharas
To identify drivers of sensitivity and resistance to Protein Arginine Methyltransferase 5 (PRMT5) inhibition, we perform a genome-wide CRISPR/Cas9 screen. We identify TP53 and RNA-binding protein MUSASHI2 (MSI2) as the top-ranked sensitizer and driver of resistance to specific PRMT5i, GSK-591, respectively. TP53 deletion and TP53R248W mutation are biomarkers of resistance to GSK-591. PRMT5 expression correlates with MSI2 expression in lymphoma patients. MSI2 depletion and pharmacological inhibition using Ro 08-2750 (Ro) both synergize with GSK-591 to reduce cell growth...
September 27, 2022: Nature Communications