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Acquired resistance to PRMT5 inhibition and the consequent collateral sensitivity to paclitaxel are both Stmn2 dependent

ABSTRACT: Acquired resistance to PRMT5 inhibition and the consequent collateral sensitivity to paclitaxel are both Stmn2 dependent

PROVIDER: PRJNA662553 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12616332.fastq.gz	Fastqsanger.gz
	SRR12616333.fastq.gz	Fastqsanger.gz
	SRR12616334.fastq.gz	Fastqsanger.gz
	SRR12616335.fastq.gz	Fastqsanger.gz
	SRR12616336.fastq.gz	Fastqsanger.gz

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Similar Datasets

Acquired resistance to PRMT5 inhibition and the consequent collateral sensitivity to paclitaxel are both Stmn2 dependent

Project description:Drug resistance is a major hurdle for the efficacy of cancer therapies. Protein arginine methyltransferase 5 (PRMT5) is an epigenetic regulator that is upregulated in most tumor types, and PRMT5 inhibitors (PRMT5i) are now in clinical trials. Here we describe the first model of resistance to PRMT5 inhibition, using cell lines derived from murine Kras-G12D;p53-null lung adenocarcinomas (LUAD). Initially, PRMT5 inhibition induced proliferation defects and apoptosis, but eventually we were able to generate numerous independent PRMT5i resistant lines. Resistance was drug-induced, not preexisting, and reflects a novel, shared transcriptional state. This state is stable, and it creates a collateral sensitivity to the taxane, paclitaxel. Accordingly, PRMT5i and paclitaxel synergistically suppress Kras-G12D;p53-null murine LUAD cells. Remarkably, a single gene Stathmin 2 (Stmn2) is required for both PRMT5i resistance and paclitaxel sensitivity. Finally, analysis of TCGA patient data showed that high Stmn2 levels correlates with good tumor responses to taxane treatment.

2021-08-01 | GSE157715 | GEO

A chemical screen identifies PRMT5 as a therapeutic vulnerability for paclitaxel-resistant triple-negative breast cancer

Project description:Paclitaxel -resistant triple negative breast cancer (TNBC) remains one of the most challenging breast cancers to treat. Using an epigenetic chemical probe screen, we uncover an acquired vulnerability of paclitaxel-resistant TNBC cells to protein arginine methyltransferases (PRMTs) inhibition. Analysis of cell lines and in-house clinical samples demonstrates that resistant cells evade paclitaxel killing through stabilizing mitotic chromatin assembly. Genetic or pharmacologic inhibition of PRMT5 alters RNA splicing, particularly intron retention of Aurora kinases B (AURKB), leading to a decrease in protein expression, and finally results in selective mitosis catastrophe in paclitaxel-resistant cells. These findings are fully recapitulated in a patient derived xenograft (PDX) model generated from a paclitaxel-resistant TNBC patient, providing the rationale for targeting PRMTs in paclitaxel-resistant TNBC.

2024-06-21 | GSE264630 | GEO

Collateral Responses to Classical Cytotoxic Chemotherapies are Heterogeneous and Sensitivities are Sparse

Project description:Chemotherapy resistance is a major obstacle to curing cancer patients. Combination drug regimens have shown promise as a method to overcome resistance; however, to date only some cancers have been cured with this method. Collateral sensitivity – the phenomenon whereby resistance to one drug is co-occurrent with sensitivity to a second drug – has been gaining traction as a promising new concept to guide rational design of combination regimens. Here we evolved over 100 subclones of the Eµ-Myc; p19ARF -/- cell line to be resistant to one of four classical chemotherapy agents: doxorubicin, vincristine, paclitaxel, and cisplatin. We then surveyed collateral responses to acquisition of resistance to these agents. Although numerous collateral sensitivities have been documented for antibiotics and targeted cancer therapies, we observed only one collateral sensitivity: half of cell lines that acquired resistance to paclitaxel also acquired a collateral sensitivity to verapamil. However, we found that the mechanism of this collateral sensitivity was unrelated to the mechanism of paclitaxel resistance. Interestingly, we observed heterogeneity in the phenotypic response to acquisition of resistance to most of the drugs we tested, most notably for paclitaxel, suggesting the existence of multiple different states of resistance. Surprisingly, this phenotypic heterogeneity in paclitaxel resistant cell lines was unrelated to transcriptomic heterogeneity among those cell lines. These features of phenotypic and transcriptomic heterogeneity must be taken into account in future studies of treated tumor subclones and in design of chemotherapy combinations.

2022-03-23 | GSE166425 | GEO

collateral effects

Project description:collateral effects

| PRJNA706668 | ENA

Gene expression associated with acquired paclitaxel resistance in ovarian cancer cell lines

Project description:Conventional frontline treatment for ovarian cancer consists of successive chemotherapy cycles of paclitaxel and platinum. Despite the initial favorable responses for most patients, chemotherapy resistance frequently leads to recurrent or refractory disease. New treatment strategies that circumvent or prevent mechanisms of resistance are needed to improve ovarian cancer therapy. We developed in vitro ovarian cancer cell line models of acquired paclitaxel resistance using 2 immortalized human ovarian cancer cell lines, OVCAR3 and TOV-21G. We also developed in vitro primary ovarian cancer organoid models using tumor tissue from 7 patients with gynecologic malignancies. Gene expression differences in resistant and sensitive lines were analyzed by RNA sequencing to identify potential mechanisms of paclitaxel resistance in primary ovarian cancer.

2021-07-02 | GSE172016 | GEO

PRMT5 is essential for sustaining normal adlut hematopoiesis

Project description:Examining the effects of PRMT5 loss on the gene expression profile of hematopoietic stem and progenitor cells We established the PRMT5 conditional KO mice, and bred the mice with Mx1 cre transgenic mice to delete PRMT5 in hematopoietic cells. We isolated hematopoetic stem and progenitor cells 3 days after PRMT5 deletion, and examined the gene expression files using RNA-sequencing.

2015-07-15 | E-GEOD-69937 | biostudies-arrayexpress

A chemical screen identifies PRMT5 as a therapeutic vulnerability for paclitaxel-resistant triple-negative breast cancer

Project description:A chemical screen identifies PRMT5 as a therapeutic vulnerability for paclitaxel-resistant triple-negative breast cancer

| PRJNA1103684 | ENA

A chemical screen identifies PRMT5 as a therapeutic vulnerability for paclitaxel-resistant triple-negative breast cancer

Project description:Through chemical probe screening, we uncovered a novel mechanism of RNA splicing in paclitaxel-resistant TNBC and identified PRMTs as therapeutic targets.

| PXD053336 |

transcriptome-wide collateral effects of Cas13d variants

Project description:The intrinsic collateral cleavage activity of Cas13d,which refers to the gRNA-independent degradation of bystander RNA, significantly limits its therapeutic potential. To extensively evaluate the collateral effects of hpCas13d genome-wide, we conducted RNA-seq analysis of the transcriptome in HEK293T cells after the transfections with dCas13d, wtCas13d, hpCas13d, and hfCas13d . Compared to dCas13d, wtCas13d with a PPIA gRNA (reported to induce the significant collateral cleavage) resulted in significant downregulations of thousands genes. In sharp contrast, hpCas13d and hfCas13d showed much less off-target genes, respectively. These findings demonstrate that hpCas13d exhibits reduced collateral activity, rendering it suitable for in vivo applications.

2024-02-28 | GSE260500 | GEO

PRMT5 inhibition by SCR-6920 leads to downregulation of HIF-1α and exhibits synergistic antitumor activity with bevacizumab in ovarian cancer

Project description:Protein arginine methyltransferase 5 (PRMT5) is a desirable anticancer target due to its extensive involvement in cellular processes associated with tumor initiation and progression. This study describes an oral PRMT5 selective inhibitor, SCR-6920, with potent inhibitory activity against multiple tumor types. Cryo-EM structure shows that SCR-6920 binds to PRMT5:MEP50 in a substrate-competitive mode with high binding affinity. Notably, RNAseq analysis links vascular endothelial growth factor (VEGF) to PRMT5 and further studies show that SCR-6920 downregulates hypoxia-inducible factor-1α (HIF-1α) expression through the ubiquitin-proteasome degradation pathway, thereby reducing downstream VEGF secretion. Further in vivo efficacy study demonstrates a synergistic effect for SCR-6920 combined with bevacizumab against ovarian cancer. Additionally, SCR-6920 improves the efficacy of clinical first-line ovarian cancer therapies (paclitaxel, docetaxel, doxorubicin, and olaparib). SCR-6920 has progressed into phase 1 clinical trials for solid tumors, and this study paves the way for its future clinical combination exploration in ovarian cancer.

2025-03-14 | GSE261629 | GEO

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