Combined CDK inhibition overcomes MEK inhibitor resistance in plexiform neurofibroma of neurofibromatosis type I
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ABSTRACT:
PROVIDER: PRJNA726198 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14360178_1.fastq.gz | Fastqsanger.gz | |||
| SRR14360178_2.fastq.gz | Fastqsanger.gz | |||
| SRR14360179_1.fastq.gz | Fastqsanger.gz | |||
| SRR14360179_2.fastq.gz | Fastqsanger.gz | |||
| SRR14360180_1.fastq.gz | Fastqsanger.gz |
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Project description:MEK1/2 inhibitors (MEKi) have recently achieved surprising success in treating unresectable plexiform neurofibromas (PNFs). However, few studies have investigated the mechanisms of MEKi resistance in PNF patients. We determined the efficacy of 6 different MEKi for treating PNFs, explored drug resistance mechanisms and identified potential combination therapies to overcome resistance. By screening drug efficacy among 6 MEKi in human NF1-deficient PNF cell lines, TAK-733 was found reduce PNF cell viability the most. We then cultured the TAK-733 resistant cells and explored potential targets for further treatment. Both high-throughput drug screening and RNA sequencing analyses of MEKi-resistant PNF cells identified cyclin-dependent kinase inhibitors (CDKi) as potential agents for PNFs. Dinaciclib, a CDKi, showed synergistic effects on MEKi-resistant cells. Coadministration of dinaciclib and TAK-733 significantly reduced cell viability, inhibited sphere formation and colony formation. Dinaciclib did not affect MEK signaling but decreased the expression of several prosurvival proteins, including survivin and CDK1, to induce apoptosis and inhibit mitosis. TAK-733/dinaciclib combination therapy induced tumor reduction in PNF patient-derived xenografts mouse models. Therefore, the combination of MEKi and CDKi may be promising for treating inoperable PNFs, especially when drug resistance exists. Our findings provide evidence for future clinical trials with MEKi-resistant PNF patients.
2022-05-01 | GSE173577 | GEO
Project description:Neurofibromatosis type 1 (NF1) is the most common autosomal dominant disorder, affecting 1 in 3,500 individuals worldwide and predisposing to cancer. Germline mutations in the NF1 gene, encoding the p21Ras GTPase-activating protein (GAP) neurofibromin, are the underlying cause for NF1. Somatic inactivation of the wild type copy of NF1 leads to deregulated Ras signaling. Clinical manifestations are diverse for NF1 patients, but the predominant lesions are plexiform neurofibroma (PNF), arising from the Schwann cell (SC) lineage. While PNF are generally benign, approximately 10% of patients will experience PN progression to highly aggressive malignant peripheral nerve sheath tumors (MPNST) with poor prognosis. There are currently no approved targeted therapies for PNF or MPNST. In this study, we used a conditional mouse model of NF1, test the multi-receptor tyrosine kinase inhibitor, cabozantinib (XL184). Mice were treated with vehicle or with cabozantinib for 3 or 7 days. Tissue was harvested, lysates prepared, and the lysate was used for kinome profiling. From cell lines or tumor tissue, protein lysates are prepared and passed over an affinity matrix consisting of Sepharose beads covalently coupled to a mixture of linker-adapted Type I kinase inhibitors. Kinase capture is reproducible and is a function of affinity for kinases for the immobilized inhibitors, expression level of the kinase, as well as the activation state of the kinase. Following affinity purification, kinases are identified and their multiplexed kinase inhibitor bead binding quantified by mass spectrometry (MIB/MS). Our goal is to identify the kinome changes in NF1 plexiform neurofibroma induced by cabozantinib treatment.
2020-11-19 | PXD019138 | Pride
Project description:Neurofibromatosis type 1 (NF1) is the most common autosomal dominant disorder, affecting 1 in 3,500 individuals worldwide and predisposing to cancer. Germline mutations in the NF1 gene, encoding the p21Ras GTPase-activating protein (GAP) neurofibromin, are the underlying cause for NF1. Somatic inactivation of the wild type copy of NF1 leads to deregulated Ras signaling. Clinical manifestations are diverse for NF1 patients, but the predominant lesions are plexiform neurofibroma (PNF), arising from the Schwann cell (SC) lineage. While PNF are generally benign, approximately 10% of patients will experience PN progression to highly aggressive malignant peripheral nerve sheath tumors (MPNST) with poor prognosis. There are currently no approved targeted therapies for PNF or MPNST. In this study, we used a conditional mouse model of NF1, test the multi-receptor tyrosine kinase inhibitor, cabozantinib (XL184). Mice were treated with vehicle or with cabozantinib for 3 or 7 days. Tissue was harvested, lysates prepared, and the lysate was used for kinome profiling. From cell lines or tumor tissue, protein lysates are prepared and passed over an affinity matrix consisting of Sepharose beads covalently coupled to a mixture of linker-adapted Type I kinase inhibitors. Kinase capture is reproducible and is a function of affinity for kinases for the immobilized inhibitors, expression level of the kinase, as well as the activation state of the kinase. Following affinity purification, kinases are identified and their multiplexed kinase inhibitor bead binding quantified by mass spectrometry (MIB/MS). Our goal is to identify the kinome changes in NF1 plexiform neurofibroma induced by cabozantinib treatment.
2023-05-18 | PXD019005 | Pride
Project description:Plexiform neurofibroma is a major contributor to morbidity in Neurofibromatosis type I (NF1) patients. Macrophages and mast cells infiltrate neurofibroma, and data from mouse models implicate these leukocytes in neurofibroma development. Anti-inflammatory therapy targeting these cell populations has been suggested as a means to prevent neurofibroma development. Here, we compare gene expression in inflamed nerves from NF1 models which invariably form neurofibroma to those with inflammation driven by EGFR overexpression which rarely progresses to neurofibroma. We find that the chemokine Cxcl10 is uniquely up-regulated in NF1 mice that invariably develop neurofibroma. Global deletion of the CXCL10 receptor, Cxcr3, prevented neurofibroma development in these neurofibroma-prone mice. Cxcr3 expression localized to T cells and dendritic cells (DCs) in both inflamed nerves and neurofibromas. These data support a heretofore unappreciated role for T cells/DCs in neurofibroma initiation.
2019-02-24 | GSE122730 | GEO
Project description:Plexiform neurofibroma is a major contributor to morbidity in Neurofibromatosis type I (NF1) patients. Macrophages and mast cells infiltrate neurofibroma, and data from mouse models implicate these leukocytes in neurofibroma development. Anti-inflammatory therapy targeting these cell populations has been suggested as a means to prevent neurofibroma development. Here, we compare gene expression in inflamed nerves from NF1 models which invariably form neurofibroma to those with inflammation driven by EGFR overexpression which rarely progresses to neurofibroma. We find that the chemokine Cxcl10 is uniquely up-regulated in NF1 mice that invariably develop neurofibroma. Global deletion of the Cxcl10 receptor Cxcr3 prevented neurofibroma development in these neurofibroma-prone mice. Cxcr3 expression localized to T cells and dendritic cells (DCs) in both inflamed nerves and neurofibromas. These data support a heretofore unappreciated role for T cells/DCs in neurofibroma initiation.
2018-11-28 | GSE122999 | GEO
Project description:Background: Neurofibromatosis 1 (NF1) is one of the most common hereditary neurocutaneous disorders. Among clinical phenotypes of NF1, cutaneous neurofibroma (cNF) and plexiform neurofibroma (pNF) display distinct clinical manifestations and pNF should be carefully followed up due to its potential for malignant transformation. However, the detailed distinct features of pNF compared to the other phenotypes in NF1 remains unclear. Objective: To elucidate whether transcriptional features are altered between cNF and pNF within the same patient. Methods: Single-cell RNA-sequencing was performed on the isolated cNF and pNF cells from the same patient. Immunohistochemical analysis was conducted on 6 cNF and 5 pNF specimens from different subjects. Results: cNF and pNF have different microenvironment and distinct transcriptional profiles. Schwann cells with robust metabolic capacity and fibroblasts with cancer-associated fibroblast-like phenotype are enriched in pNF, while CD8 T cells with tissue residency markers are endowed in cNF. The density of CD8 T cells is histologically augmented in cNF. Conclusion: cNF and pNF, the different NF phenotypes in NF1, are transcriptionally distinct in terms of various involved cell types including immune cells.
2023-09-30 | GSE218493 | GEO
Project description:The MEK inhibitor selumetinib induces objective responses and provides clinical benefit in children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PNs). To evaluate whether similar outcomes were possible in adult patients, in whom PN growth is generally slower than in pediatric patients, an open-label phase 2 study of selumetinib in adults with NF1 PNs was conducted. Correlative analysis included extraction of RNA followed by sequencing. Samples include paired specimens collected before and on treatment.
2024-10-07 | GSE277520 | GEO
Project description:To define alterations early in tumor formation, we studied nerve tumors in neurofibromatosis 1 (NF1), a tumor predisposition syndrome in which affected individuals develop plexiform neurofibroma (PN). These benign tumors are driven by NF1 loss in Schwann cells (SC). By comparing normal nerve cells to PN cells using single cell and bulk RNA sequencing, we identified changes in five SC populations, including a de novo Schwann cell progenitor-like population. Long after Nf1 loss, SC populations developed PN-specific expression of Dcn, Postn, and CD74, and showed dramatic expansion of immune and stromal cell populations; in human PN, immune and stromal cells comprised 90% of cells. Label transfer enabled verification of each SC population and predicted tumor unique patterns of cell-cell communication in each SC population. We identified PROS-AXL, FGF-FGFR, and MIF-CD74 and its effector pathway NFkB as deregulated in NF1 SC populations, including SCP-like cells. Each receptor-ligand pair was predicted to influence surrounding cells in mouse and human. These findings highlight remarkable changes in all PN cells driven by loss of NF1 in multiple types of SCs and identify therapeutic targets for PN.
2022-11-23 | GSE181985 | GEO
Project description:Patients with neurofibromatosis type 1 (NF1) develop benign plexiform neurofibromas that frequently progress to become malignant peripheral nerve sheath tumors (MPNSTs). A genetically engineered mouse model that accurately models plexiform neurofibroma-MPNST progression would facilitate the identification of somatic mutations driving this process. We have previously reported that transgenic mice overexpressing the growth factor neuregulin-1 in Schwann cells (P0-GGF?3 mice) develop MPNSTs. To determine whether P0-GGF?3 mice accurately model neurofibroma-MPNST progression, cohorts of these animals were followed to death and necropsied. 94% of the mice developed multiple neurofibromas, with 70% carrying smaller numbers of MPNSTs; nascent MPNSTs were identified within neurofibromas, suggesting that these sarcomas arise from neurofibromas. Although neurofibromin expression was maintained, P0-GGF?3 MPNSTs, like human NF1-associated MPNSTs, demonstrated Ras hyperactivation. P0-GGF?3 MPNSTs also showed abnormalities in the p16INK4A-cyclin D/CDK4-Rb and p19ARF-Mdm-p53 pathways analogous to their human counterparts. Array comparative genomic hybridization (CGH) demonstrated reproducible chromosomal alterations in P0-GGF?3 MPNST cells (including universal chromosome 11 gains) and focal gains and losses affecting 39 genes previously implicated in neoplasia (e.g., Pten, Tpd52, Myc , Gli1, Xiap, Bbc3/PUMA). Array CGH also identified recurrent focal copy number variations affecting genes not previously linked to neurofibroma or MPNST pathogenesis. We conclude that P0-GGF?3 mice represent a robust model of neurofibroma-MPNST progression that can be used to identify novel genes driving neurofibroma and MPNST pathogenesis. Array CGH comparison of malignant peripheral nerve sheath tumor (MPNST) cells vs non-neoplastic Schwann cells
2012-12-31 | E-GEOD-40212 | biostudies-arrayexpress
Project description:Selumetinib in adults with NF1 and inoperable plexiform neurofibroma
| PRJNA1162564 | ENA