TP53 mutations and RNA-binding protein MUSASHI-2 drive resistance to PRMT5-targeted therapy in B-cell lymphoma.

Autor: Erazo T; Molecular Pharmacology Program, Experimental Therapeutics Center and Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Evans CM; Molecular Pharmacology Program, Experimental Therapeutics Center and Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Department of Pharmacology, Weill Cornell School of Medical Sciences, New York, NY, USA., Zakheim D; Gene Editing and Screening Core, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Chu EL; Molecular Pharmacology Program, Experimental Therapeutics Center and Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Refermat AY; Gene Editing and Screening Core, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Asgari Z; Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Yang X; Molecular Pharmacology Program, Experimental Therapeutics Center and Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Da Silva Ferreira M; Molecular Pharmacology Program, Experimental Therapeutics Center and Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Mehta S; Gene Editing and Screening Core, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Russo MV; Gene Editing and Screening Core, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Knezevic A; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Zhang XP; Epigenetics Research Unit, GlaxoSmithKline, Collegeville, PA, 19426, USA., Chen Z; Division of Biostatistics and Epidemiology, Weill Cornell Medicine, New York, NY, 10021, USA., Fennell M; Gene Editing and Screening Core, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Garippa R; Gene Editing and Screening Core, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Seshan V; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA., de Stanchina E; Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Barbash O; Epigenetics Research Unit, GlaxoSmithKline, Collegeville, PA, 19426, USA., Batlevi CL; Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Leslie CS; Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Melnick AM; Division of Hematology and Medical Oncology, Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY, USA., Younes A; Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. anas.younes@astrazeneca.com., Kharas MG; Molecular Pharmacology Program, Experimental Therapeutics Center and Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. kharasm@mskcc.org.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Sep 27; Vol. 13 (1), pp. 5676. Date of Electronic Publication: 2022 Sep 27.
DOI: 10.1038/s41467-022-33137-8
Abstrakt: 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 TP53 R248W 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. Ro reduces MSI2 binding to its global targets and dual treatment of Ro and PRMT5 inhibitors result in synergistic gene expression changes including cell cycle, P53 and MYC signatures. Dual MSI2 and PRMT5 inhibition further blocks c-MYC and BCL-2 translation. BCL-2 depletion or inhibition with venetoclax synergizes with a PRMT5 inhibitor by inducing reduced cell growth and apoptosis. Thus, we propose a therapeutic strategy in lymphoma that combines PRMT5 with MSI2 or BCL-2 inhibition.
(© 2022. The Author(s).)
Databáze: MEDLINE
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