Resistance to PRMT5-targeted therapy in mantle cell lymphoma.

TitleResistance to PRMT5-targeted therapy in mantle cell lymphoma.
Publication TypeJournal Article
Year of Publication2024
AuthorsLong MElizabeth, Koirala S, Sloan S, Brown-Burke F, Weigel C, Villagomez L, Corps K, Sharma A, Hout I, Harper M, Helmig-Mason JB, Tallada S, Chen Z, Scherle P, Vaddi K, Chen-Kiang S, Di Liberto M, Meydan C, Foox J, Butler D, Mason C, Alinari L, Blaser BW, Baiocchi R
JournalBlood Adv
Date Published2024 Jan 09
KeywordsAdult, Animals, Cell Line, Tumor, Enzyme Inhibitors, Humans, Lymphoma, Mantle-Cell, Mechanistic Target of Rapamycin Complex 1, Mice, Neoplasm Recurrence, Local, Protein-Arginine N-Methyltransferases, Signal Transduction

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.

Alternate JournalBlood Adv
PubMed ID37782774
PubMed Central IDPMC10787272
Grant ListF32 CA265099 / CA / NCI NIH HHS / United States
P01 CA214274 / CA / NCI NIH HHS / United States
P30 CA016058 / CA / NCI NIH HHS / United States
K22 CA160587 / CA / NCI NIH HHS / United States
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Related Faculty: 
Selina Chen-Kiang, Ph.D.

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