Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

PRMT5 inhibition in MCL

ABSTRACT: To identify the mechanistic underpinning of the anti-tumor activity of PRMT5 inhibition in MCL, we explored transcriptomic profiles of PDX-AA cells treated in vivo for 2 weeks with PRT-382, ibrutinib, or vehicle control (n=3/group).

ORGANISM(S): Homo sapiens

PROVIDER: GSE220936 | GEO | 2023/09/27

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Resistance to PRMT5-targeted therapy in mantle cell lymphoma

Project description: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.

2024-04-09 | GSE229517 | GEO

Resistance to PRMT5 Inhibitor Targeted Therapy in MCL [WES]

Project description:To identify the genomic changes underlying PRMT5 inhibitor resistance in MCL cell lines and MCL PDX

2023-12-30 | GSE240725 | GEO

Resistance to PRMT5 Inhibitor Targeted Therapy in MCL [RNA-seq]

Project description:To identify the transcriptomic changes underlying acquired PRMT5 inhibitor resistance in MCL cell lines (n=3/group) and MCL PDX

2023-12-30 | GSE240555 | GEO

PRMT5 inhibition in MCL

Project description:PRMT5 inhibition in MCL

| PRJNA912113 | ENA

Resistance to PRMT5 Inhibitor Targeted Therapy in MCL

Project description:Resistance to PRMT5 Inhibitor Targeted Therapy in MCL

| PRJNA1005102 | ENA

Resistance to PRMT5 Inhibitor Targeted Therapy in MCL [WES]

Project description:Resistance to PRMT5 Inhibitor Targeted Therapy in MCL [WES]

| PRJNA1005107 | ENA

Transcriptional responses of mantle cell lymphoma (MCL) lines to IKKB inhibition

Project description:MCL cell lines were treated with DMSO or 5uM AFN700 for 20hrs This experiment is designed to see if NFKB-target genes are downregulated by inhibition of IKKB in MCL cell lines that are insensitive to ibrutinib (BTK inhibitor) or sotrastaurin (PKC inhibitor) MCL cells were seeded in 6well dishes and treated for 20hrs with DMSO or 5uM AFN700

2013-12-01 | E-GEOD-52434 | biostudies-arrayexpress

Resistance to PRMT5 Inhibitor Targeted Therapy in MCL [RNA-seq]

Project description:Resistance to PRMT5 Inhibitor Targeted Therapy in MCL [RNA-seq]

| PRJNA1004222 | ENA

XPO1 inhibition antagonizes MCL via nuclear retention of IkB: Selinexor demonstrates antitumor activities in both ibr-sensitive and ibr-resistant tumor cells

Project description:Inhibition of BCR signaling through BTK inhibitor, ibrutinib, has generated a remarkable response in mantle cell lymphoma (MCL). However, approximately one-third of the patients do not respond well to the drug and disease relapse on ibrutinib is nearly universal. Alternative therapeutic strategies aimed to prevent and overcome ibrutinib resistance are needed. We compared and contrasted the effects of selinexor, a selective inhibitor of nuclear export, with ibrutinib in six MCL cell lines that display differential intrinsic sensitivity to ibrutinib. We found that selinexor had a broader anti-tumor activity in MCL than ibrutinib. MCL cell lines resistant to ibrutinib remained sensitive to selinexor. We showed that selinexor induced apoptosis/cell cycle arrest and XPO-1 knockdown also retarded cell growth. Further, down-regulation of the NF-B gene signature, as opposed to BCR signature, was a common feature that underlies the response of MCL to both selinexor and ibrutinib. Meanwhile, unaltered NF-B was associated with ibrutinib resistance. Mechnistically, selinexor induced nuclear retention of IB that was accompanied by the reduction of DNA binding activity of NF-B suggesting that NF-B is trapped in an inhibitory complex. Co-immunoprecipitation confirmed that p65 of NF-B and IB were physically associated. In primary MCL tumors, we further demonstrated that the number of cells with IB nuclear retention was linearly correlated with the degree of apoptosis. Our data highlight the role of NF-B pathway in drug response to ibrutinib and selinexor and show the potential of using selinexor to prevent and overcome intrinsic ibrutinib resistance through NF-B inhibition.

2018-07-10 | GSE116810 | GEO

Transcriptional responses of mantle cell lymphoma (MCL) lines to IKKB inhibition

2013-12-01 | GSE52434 | GEO