Pharmacogenomic synthetic lethal screens reveal hidden vulnerabilities and new therapeutic approaches for treatment of NF1-associated tumor
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1090069 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28399431_1.fastq.gz | Fastqsanger.gz | |||
| SRR28399431_2.fastq.gz | Fastqsanger.gz | |||
| SRR28399432_1.fastq.gz | Fastqsanger.gz | |||
| SRR28399432_2.fastq.gz | Fastqsanger.gz | |||
| SRR28399433_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 102 |
Similar Datasets
Project description:Neurofibromatosis Type 1 (NF1) is a common cancer predisposition syndrome, caused by heterozygous loss of function mutations in the tumor suppressor gene NF1. Individuals with NF1 develop benign tumors of the peripheral nervous system (neurofibromas), originating from the Schwann cell linage after somatic loss of the wild type NF1 allele, some of which progress further to malignant peripheral nerve sheath tumors (MPNST). There is only one FDA approved targeted therapy for symptomatic plexiform neurofibromas and none approved for MPNST. The genetic basis of NF1 syndrome makes associated tumors ideal for using synthetic drug sensitivity approaches to uncover vulnerabilities. We developed a drug discovery pipeline to identify therapeutics for NF1-related tumors using isogeneic pairs of NF1 proficient and deficient immortalized human Schwann cells. We utilized these in a large-scale high throughput screen (HTS) for drugs that preferentially kill NF1 deficient cells, which identified 23 compounds capable of killing NF1 deficient Schwann cells with selectivity. Multiple hits from this screen clustered into classes defined by method of action. Four clinically interesting drugs from these classes were tested in vivo using both a genetically engineered mouse model of high-grade peripheral nerve sheath tumors and human MPNST xenografts. All trugs tested showed single agent efficacy in these models as well as significant synergy when used in combination with the MEK inhibitor selumetinib. This HTS platform has yielded novel therapeutically relevant compounds for the treatment of NF1-associated tumors and can serve as a tool to rapidly evaluate new compounds and combinations in the future.
2024-03-21 | GSE262030 | GEO
Project description:Neurofibromatosis Type 1 (NF1) is a common cancer predisposition syndrome, caused by heterozygous loss of function mutations in the tumor suppressor gene NF1. Individuals with NF1 develop benign tumors of the peripheral nervous system (neurofibromas), originating from the Schwann cell linage after somatic loss of the wild type NF1 allele, some of which progress further to malignant peripheral nerve sheath tumors (MPNST). There is only one FDA approved targeted therapy for symptomatic plexiform neurofibromas and none approved for MPNST. The genetic basis of NF1 syndrome makes associated tumors ideal for using synthetic drug sensitivity approaches to uncover therapeutic vulnerabilities. We developed a drug discovery pipeline to identify therapeutics for NF1-related tumors using isogeneic pairs of NF1-proficient and deficient immortalized human Schwann cells. We utilized these in a large-scale high throughput screen (HTS) for drugs that preferentially kill NF1-deficient cells, through which we identified 23 compounds capable of killing NF1-deficient Schwann cells with selectivity. Multiple hits from this screen clustered into classes defined by method of action. Four clinically interesting drugs from these classes were tested in vivo using both a genetically engineered mouse model of high-grade peripheral nerve sheath tumors and human MPNST xenografts. All drugs tested showed single agent efficacy in these models as well as significant synergy when used in combination with the MEK inhibitor selumetinib. This HTS platform yielded novel therapeutically relevant compounds for the treatment of NF1-associated tumors and can serve as a tool to rapidly evaluate new compounds and combinations in the future.
| S-EPMC10996510 | biostudies-literature
Project description:Patient-derived xenografts and matched cell lines identify pharmacogenomic vulnerabilities in colorectal cancer
| PRJEB33640 | ENA
Project description:Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant embryonal brain tumor driven by genetic alterations inactivating the SMARCB1 or, less commonly, the SMARCA4 gene. Large-scale molecular profiling studies have identified distinct molecular subtypes termed AT/RT-TYR, -SHH and -MYC. Despite the increasing knowledge of AT/RT biology, curative treatment options are still lacking for certain risk groups and outcomes of these patients remain poor. We performed an in vitro high-throughput drug screen of 768 small molecule drugs covering conventional chemotherapeutic agents and late-stage developmental drugs in 13 AT/RT cell lines and determined intra- and inter-entity differential responses to unravel specific vulnerabilities. Our data demonstrated in vitro preferential activity of mitogen-activated protein kinase kinase (MEK) and mouse double minute 2 homolog (MDM2) inhibitors in AT/RT cell lines compared to other high-grade brain tumor cell lines including medulloblastoma and malignant glioma models. Moreover, we were able to link distinct drug response patterns to AT/RT molecular subtypes through integration of drug response data with large-scale DNA methylation and RNASeq-based expression profiles. Subtype-dependent drug response profiles demonstrated sensitivity of AT/RT-SHH cell lines to B-cell lymphoma 2 (BCL2) and heat shock protein 90 (HSP90) inhibitors, and increased activity of microtubule inhibitors, kinesin spindle protein (KSP) inhibitors, and the eukaryotic translation initiation factor 4E (eIF4E) inhibitor briciclib in a subset of AT/RT-MYC cell lines. In summary, our in vitro pharmacogenomic approach revealed preclinical evidence of tumor type- and subtype-specific therapeutic vulnerabilities in AT/RT cell lines that may inform future in vivo and clinical evaluations of novel pharmacological strategies.
2025-02-26 | GSE282972 | GEO
Project description:Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant embryonal brain tumor driven by genetic alterations inactivating the SMARCB1 or, less commonly, the SMARCA4 gene. Large-scale molecular profiling studies have identified distinct molecular subtypes termed AT/RT-TYR, -SHH and -MYC. Despite the increasing knowledge of AT/RT biology, curative treatment options are still lacking for certain risk groups and outcomes of these patients remain poor. We performed an in vitro high-throughput drug screen of 768 small molecule drugs covering conventional chemotherapeutic agents and late-stage developmental drugs in 13 AT/RT cell lines and determined intra- and inter-entity differential responses to unravel specific vulnerabilities. Our data demonstrated in vitro preferential activity of mitogen-activated protein kinase kinase (MEK) and mouse double minute 2 homolog (MDM2) inhibitors in AT/RT cell lines compared to other high-grade brain tumor cell lines including medulloblastoma and malignant glioma models. Moreover, we were able to link distinct drug response patterns to AT/RT molecular subtypes through integration of drug response data with large-scale DNA methylation and RNASeq-based expression profiles. Subtype-dependent drug response profiles demonstrated sensitivity of AT/RT-SHH cell lines to B-cell lymphoma 2 (BCL2) and heat shock protein 90 (HSP90) inhibitors, and increased activity of microtubule inhibitors, kinesin spindle protein (KSP) inhibitors, and the eukaryotic translation initiation factor 4E (eIF4E) inhibitor briciclib in a subset of AT/RT-MYC cell lines. In summary, our in vitro pharmacogenomic approach revealed preclinical evidence of tumor type- and subtype-specific therapeutic vulnerabilities in AT/RT cell lines that may inform future in vivo and clinical evaluations of novel pharmacological strategies.
2025-02-26 | GSE282878 | GEO
Project description:One of the major primary features of the neurocutaneous genetic disorder Neurofibromatosis type 1 are the hyperpigmentary café-au-lait macules where dysregulation of melanocyte development, proliferation and differentiation is considered to play a key etiopathogenic role. To gain better insight in the possible role of the tumor suppressor gene NF1, a transcriptomic microarray analysis was performed on human NF1 heterozygous (NF1+/-) melanocytes of a Neurofibromatosis type 1 patient and NF1 wild type (NF1+/+) melanocytes of a healthy control patient, both cultured from normally pigmented and hyperpigmented lesional café-au-lait skin. Out of 13,850 unique genes, a total of 137 had a significant twofold or more up- (72) or down-regulated (65) expression in NF1+/- melanocytes compared to NF1+/+ melanocytes (genotype effect). Considering possible intrinsic genetic variation in lesional skin, melanocytes showed a total of 51 genes having a significant twofold or more up- (37) or down-regulated (14) expression when they were cultured from hyperpigmentary café-au-lait skin compared to normally pigmented skin (lesional skin type effect). NF1+/- café-au-lait skin melanocytes showed 468 genes with a significant two-fold or more up- (183) or down-regulated (285) expression going beyond the sum of the separate main effects (interaction). Detailed analysis enabled the identification of several modulated genes in NF1+/- (café-au-lait skin) melanocytes, mainly involved in controlling cell proliferation and cell maintenance, in cell adhesion and, surprisingly, in the immune response. An interesting finding was that a high number of transcription factor genes were differentially modulated, among which a specific subset - important in melanocyte-lineage development - showed downregulation in a transcriptional cis-regulatory network governing the activation of the melanocyte-specific dopachrome tautomerase (DCT) gene.
2005-02-05 | E-MEXP-258 | biostudies-arrayexpress
Project description:Analysis of the effect of NF1 second hit mutation to the reading of the whole human genome by comparing the gene expression profiles of neurofibroma derived Schwann cell cultures representing two different NF1 genotypes (NF1+/- and NF1-/-).
2016-12-22 | GSE32029 | GEO
Project description:The goal of the study was to profile protein interaction neighborhood of NF1 by expressing NF1-APEX and profiling biotinylated proteins in proximity of NF1. Interactions were assessed at basal conditions or in the context of MEK inhibition with selumetinib.
2025-06-17 | PXD064557 | Pride
Project description:NF1 loss-of-function mutations are enriched in hormone receptor positive (HR+) metastatic breast cancer (MBC) and mediate endocrine therapy resistance. To identify therapeutic vulnerabilities in this context, we performed CRISPR/Cas9 screens in wildtype and NF1 knockout isogenic HR+ models and identified NR2F2, an orphan nuclear receptor, to be essential specifically in NF1 loss cells. The NR2F2 dependence was induced as a consequence of NR2F2 upregulation via the activation of the MAPK pathway in these cells. Enforced overexpression of NR2F2 was sufficient to confer endocrine therapy resistance in the absence of NF1 loss, while of NR2F2 knockout or knockdown could enhance the efficacy of endocrine therapies in NF1 WT and NF1 loss models. Mechanistically, our comprehensive multi-omics approaches revealed that NR2F2 modulates chromatin accessibility and regulates ER-dependent transcription through its interaction with ER, transcriptional coregulators and chromatin remodelers at chromatin. Specifically, increased NR2F2 in NF1 loss cells dramatically enhanced the association with transcriptional corepressors, which resulted in attenuation of chromatin accessibility and ER occupancy, and impaired ER transcriptional program. Our findings identify the nuclear receptor NR2F2 as a downstream effector of NF1 loss, and it is essential and potentially druggable mediator of endocrine therapy resistance. We performed chromatin accessibility profiling analysis using data obtained from ATAC-seq of MCF7 sgNT, sgNF1, sgNR2F2 and double knockout (DKO) cells.
2022-11-10 | GSE217415 | GEO
Project description:NF1 loss-of-function mutations are enriched in hormone receptor positive (HR+) metastatic breast cancer (MBC) and mediate endocrine therapy resistance. To identify therapeutic vulnerabilities in this context, we performed CRISPR/Cas9 screens in wildtype and NF1 knockout isogenic HR+ models and identified NR2F2, an orphan nuclear receptor, to be essential specifically in NF1 loss cells. The NR2F2 dependence was induced as a consequence of NR2F2 upregulation via the activation of the MAPK pathway in these cells. Enforced overexpression of NR2F2 was sufficient to confer endocrine therapy resistance in the absence of NF1 loss, while of NR2F2 knockout or knockdown could enhance the efficacy of endocrine therapies in NF1 WT and NF1 loss models. Mechanistically, our comprehensive multi-omics approaches revealed that NR2F2 modulates chromatin accessibility and regulates ER-dependent transcription through its interaction with ER, transcriptional coregulators and chromatin remodelers at chromatin. Specifically, increased NR2F2 in NF1 loss cells dramatically enhanced the association with transcriptional corepressors, which resulted in attenuation of chromatin accessibility and ER occupancy, and impaired ER transcriptional program. Our findings identify the nuclear receptor NR2F2 as a downstream effector of NF1 loss, and it is essential and potentially druggable mediator of endocrine therapy resistance. We performed gene expression profiling analysis using data obtained from RNA-seq of MCF7 sgNT, sgNF1, sgNR2F2 and double knockout (DKO) cells under different conditions.
2023-06-08 | GSE234074 | GEO