PMID- 37782774 OWN - NLM STAT- MEDLINE DCOM- 20240101 LR - 20240410 IS - 2473-9537 (Electronic) IS - 2473-9529 (Print) IS - 2473-9529 (Linking) VI - 8 IP - 1 DP - 2024 Jan 9 TI - Resistance to PRMT5-targeted therapy in mantle cell lymphoma. PG - 150-163 LID - 10.1182/bloodadvances.2023010554 [doi] AB - Mantle cell lymphoma (MCL) is an incurable B-cell non-Hodgkin lymphoma, and patients who relapse on targeted therapies have poor prognosis. Protein arginine methyltransferase 5 (PRMT5), an enzyme essential for B-cell transformation, drives multiple oncogenic pathways and is overexpressed in MCL. Despite the antitumor activity of PRMT5 inhibition (PRT-382/PRT-808), drug resistance was observed in a patient-derived xenograft (PDX) MCL model. Decreased survival of mice engrafted with these PRMT5 inhibitor-resistant cells vs treatment-naive cells was observed (P = .005). MCL cell lines showed variable sensitivity to PRMT5 inhibition. Using PRT-382, cell lines were classified as sensitive (n = 4; 50% inhibitory concentration [IC50], 20-140 nM) or primary resistant (n = 4; 340-1650 nM). Prolonged culture of sensitive MCL lines with drug escalation produced PRMT5 inhibitor-resistant cell lines (n = 4; 200-500 nM). This resistant phenotype persisted after prolonged culture in the absence of drug and was observed with PRT-808. In the resistant PDX and cell line models, symmetric dimethylarginine reduction was achieved at the original PRMT5 inhibitor IC50, suggesting activation of alternative resistance pathways. Bulk RNA sequencing of resistant cell lines and PDX relative to sensitive or short-term-treated cells, respectively, highlighted shared upregulation of multiple pathways including mechanistic target of rapamycin kinase [mTOR] signaling (P < 10-5 and z score > 0.3 or < 0.3). Single-cell RNA sequencing analysis demonstrated a strong shift in global gene expression, with upregulation of mTOR signaling in resistant PDX MCL samples. Targeted blockade of mTORC1 with temsirolimus overcame the PRMT5 inhibitor-resistant phenotype, displayed therapeutic synergy in resistant MCL cell lines, and improved survival of a resistant PDX. CI - (c) 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. FAU - Long, Mackenzie Elizabeth AU - Long ME AD - Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH. AD - Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH. FAU - Koirala, Shirsha AU - Koirala S AD - Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH. FAU - Sloan, Shelby AU - Sloan S AD - Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH. AD - Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH. FAU - Brown-Burke, Fiona AU - Brown-Burke F AD - Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH. FAU - Weigel, Christoph AU - Weigel C AD - Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH. FAU - Villagomez, Lynda AU - Villagomez L AUID- ORCID: 0000-0001-7179-9460 AD - Division of Hematology and Oncology, Department of Pediatrics, The Ohio State University and Nationwide Children's Hospital, Columbus, OH. FAU - Corps, Kara AU - Corps K AD - Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH. FAU - Sharma, Archisha AU - Sharma A AD - Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH. FAU - Hout, Ian AU - Hout I AD - Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH. FAU - Harper, Margaret AU - Harper M AD - Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH. FAU - Helmig-Mason, JoBeth AU - Helmig-Mason J AD - Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH. FAU - Tallada, Sheetal AU - Tallada S AD - Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH. FAU - Chen, Zhengming AU - Chen Z AD - Division of Biostatistics, Department of Population Health Sciences, Weill Cornell Medicine, New York, NY. FAU - Scherle, Peggy AU - Scherle P AD - Prelude Therapeutics, Wilmington, DE. FAU - Vaddi, Kris AU - Vaddi K AD - Prelude Therapeutics, Wilmington, DE. FAU - Chen-Kiang, Selina AU - Chen-Kiang S AD - Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY. FAU - Di Liberto, Maurizio AU - Di Liberto M AD - Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY. FAU - Meydan, Cem AU - Meydan C AUID- ORCID: 0000-0002-0663-6216 AD - Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY. FAU - Foox, Jonathan AU - Foox J AD - Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY. FAU - Butler, Daniel AU - Butler D AUID- ORCID: 0000-0002-3687-8419 AD - Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY. FAU - Mason, Christopher AU - Mason C AD - Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY. FAU - Alinari, Lapo AU - Alinari L AD - Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH. FAU - Blaser, Bradley W AU - Blaser BW AUID- ORCID: 0000-0002-3168-5423 AD - Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH. FAU - Baiocchi, Robert AU - Baiocchi R AUID- ORCID: 0000-0002-1619-4853 AD - Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH. LA - eng GR - R01 DK128238/DK/NIDDK NIH HHS/United States GR - F32 CA265099/CA/NCI NIH HHS/United States GR - K22 CA160587/CA/NCI NIH HHS/United States GR - P30 CA016058/CA/NCI NIH HHS/United States GR - P01 CA214274/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Blood Adv JT - Blood advances JID - 101698425 RN - 0 (Enzyme Inhibitors) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.1.1.319 (PRMT5 protein, human) RN - EC 2.1.1.319 (Protein-Arginine N-Methyltransferases) SB - IM MH - Humans MH - Mice MH - Animals MH - Adult MH - *Lymphoma, Mantle-Cell/drug therapy/genetics/pathology MH - Cell Line, Tumor MH - Neoplasm Recurrence, Local MH - Signal Transduction MH - Enzyme Inhibitors/therapeutic use MH - Mechanistic Target of Rapamycin Complex 1/metabolism MH - Protein-Arginine N-Methyltransferases/genetics/metabolism PMC - PMC10787272 COIS- Conflict-of-interest disclosure: P.S. and K.V. report employment with Prelude Therapeutics. K.V. and P.S. report stock holdings in Prelude Therapeutics. R.B. reports research support from Prelude Therapeutics. The remaining authors declare no competing financial interests. EDAT- 2023/10/02 18:41 MHDA- 2024/01/02 11:46 PMCR- 2023/10/04 CRDT- 2023/10/02 15:03 PHST- 2023/09/04 00:00 [accepted] PHST- 2023/05/18 00:00 [received] PHST- 2024/01/02 11:46 [medline] PHST- 2023/10/02 18:41 [pubmed] PHST- 2023/10/02 15:03 [entrez] PHST- 2023/10/04 00:00 [pmc-release] AID - 498204 [pii] AID - 10.1182/bloodadvances.2023010554 [doi] PST - ppublish SO - Blood Adv. 2024 Jan 9;8(1):150-163. doi: 10.1182/bloodadvances.2023010554.