N-acetylcysteine overcomes NF1-loss driven resistance to PI3K alpha inhibition in breast cancer [ATAC-seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE207513 | GEO | 2023/03/16
REPOSITORIES: GEO
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Project description:The aim of our study was to investigate PIK3CA collaborative mutations that result in resistance to BYL719, a PI3Kα selective inhibitor. One of the tumor suppressor genes discovered was neurofibromin 1 (NF1). Using shRNA-mediated knockdown and CRISPR/Cas9-mediated knockout of NF1 in murine and human PIK3CAH1047R cell lines and a patient derived xenograft organoid model, we found that NF1 loss reduces sensitivity to PI3Kα inhibition. By looking at differentially expressed genes we wanted to investigate the effect of NF1 KO in T47D cells and if they respond differentially to BYL719 compared to the T47D CTRL cells.
2023-03-16 | GSE207512 | GEO
Project description:The aim of our study was to investigate PIK3CA collaborative mutations that result in resistance to BYL719, a PI3Kα selective inhibitor. One of the tumor suppressor genes discovered was neurofibromin 1 (NF1). Using shRNA-mediated knockdown and CRISPR/Cas9-mediated knockout of NF1 in murine and human PIK3CAH1047R cell lines and a patient derived xenograft organoid model, we found that NF1 loss reduces sensitivity to PI3Kα inhibition. By looking at differentially expressed genes we wanted to investigate the effect of NF1 KO in T47D cells and if they respond differentially to BYL719 compared to the T47D CTRL cells.
2023-03-16 | GSE207514 | GEO
Project description:Breast cancer is the second most common cancer type worldwide, representing 25% of all cancers in women. PIK3CA is one of the most frequently mutated genes in breast cancer and mutations result in constitutive activation of the PI3K/mTOR pathway. More than 30 inhibitors against PI3K/mTOR are being tested in clinical trials, however, resistance mechanisms evolve frequently resulting in disease progression. The aim of our study was to investigate PIK3CA collaborative mutations that result in resistance to BYL719, a PI3Kα selective inhibitor. For this purpose, we used a genome-wide PiggyBac transposon mediated mutagenesis screen in a PIK3CAH1047R mutated murine tumor model. One of the tumor suppressor genes discovered was neurofibromin 1 (NF1). Using shRNA-mediated knockdown and CRISPR/Cas9-mediated knockout of NF1 in murine and human PIK3CAH1047R cell lines and a patient derived xenograft organoid model, we found that NF1 loss reduces sensitivity to PI3Kα inhibition. Additionally, we find that loss of NF1 correlates with enhanced glycolysis and lower levels of ROS. Unexpectedly, treatment with NAC sensitized NF1 KO cells to PI3K inhibition in vitro, and in vivo. Global phospho-proteomics indicated that the combination with NAC enhances the inhibitory effect of PI3K inhibition on mTOR signaling, which inhibits proliferation of NF1 KO tumor cells. This raises the interesting possibility to combine PI3K inhibition with NAC especially in NF1 loss tumors
2023-03-30 | PXD034644 | Pride
Project description:Neurofibromatosis type 1 (NF1) is a multi-system disease caused by mutations in the NF1 gene encoding a Ras-GAP protein, neurofibromin, which negatively regulates Ras signalling. Besides neuroectodermal malformations and tumours, the skeletal system is often affected (e.g. scoliosis and long bone dysplasia), demonstrating the importance of neurofibromin for development and maintenance of the musculoskeletal system. Here we focus on the role of neurofibromin in skeletal muscle development. Nf1 gene inactivation in the early limb bud mesenchyme using Prx1-cre (Nf1Prx1) resulted in muscle dystrophy characterised by fibrosis, reduced number of muscle fibres, and reduced muscle force. To gain insight into the molecular changes of the observed muscle dystrophy and fibrosis and to compare these with other known muscle dystrophies, we performed transcriptional profiling of the entire triceps muscles of threemonth-old wild type (wt) and mutant animals using Affymetrix high-density microrrays. We analyzed triceps muscles from 4 three-month-old wt controls and 4 three-month-old Nf1Prx1 mice using the Affymetrix Mouse Gene 1.0 ST platform. Array data was processed by the Affymetrix Exon Array Computational Tool. RNA isolated from each animal was hybridized to a separate microarray.
2011-05-18 | E-GEOD-29343 | biostudies-arrayexpress
Project description:Neurofibromatosis type 1 (NF1) is a multi-system disease caused by mutations in the NF1 gene encoding a Ras-GAP protein, neurofibromin, which negatively regulates Ras signalling. Besides neuroectodermal malformations and tumours, the skeletal system is often affected (e.g. scoliosis and long bone dysplasia), demonstrating the importance of neurofibromin for development and maintenance of the musculoskeletal system. Here we focus on the role of neurofibromin in skeletal muscle development. Nf1 gene inactivation in the early limb bud mesenchyme using Prx1-cre (Nf1Prx1) resulted in muscle dystrophy characterised by fibrosis, reduced number of muscle fibres, and reduced muscle force. To gain insight into the molecular changes of the observed muscle dystrophy and fibrosis and to compare these with other known muscle dystrophies, we performed transcriptional profiling of the entire triceps muscles of threemonth-old wild type (wt) and mutant animals using Affymetrix high-density microrrays.
2011-05-18 | GSE29343 | GEO
Project description:Analysis of gene expression in pathologically confirmed glioblastoma (GBM) samples. These data were used to test a classifier that was generated to distinguish GBM tumor samples with loss of neurofibromin 1 (NF1) function
2017-02-01 | GSE85033 | GEO
Project description:Heterotopic ossification (HO) occurs following mechanical trauma, burns, or congenitally in patients suffering from fibrodysplasia ossificans progressiva (FOP). Recently, we demonstrated that inhibitors of phosphatidyl-inositol 3-kinase alpha (PI3Kα), including the already marketed BYL719/Alpelisib/Piqray, may become a useful therapy for patients undergoing HO. In this study, we have confirmed these results and optimized the timing of administration of BYL719. We found that BYL719 effectively prevents HO when administered even up to three to seven days after injury. We demonstrate in cell cultures and in a mouse model of HO, that the major actions of BYL719 are on-target effects through inhibition of PI3Kα, without directly affecting ACVR1/ALK2 kinase activity. In vivo, we found that lack of PI3Kα in progenitors at injury sites is sufficient to prevent HO. Moreover, time course assays in HO lesions demonstrate that BYL719 not only blocks osteochondroprogenitor specification, but also reduces the inflammatory response. BYL719 inhibits the migration, the proliferation, and the expression of pro-inflammatory cytokines in monocytes and mast cells, suggesting that BYL719 hampers the hyper-inflammatory status of HO lesions. As part of this study, we have conducted bulk RNA sequencing using human mesenchymal stem cells (hMSCs) expressing ACVR1/ALK2-R206H to assess molecular effectors driving the therapeutic potential of BYL719 in FOP. Altogether, these results highlight the potential of PI3Kα inhibition as a safe and effective therapeutic strategy for HO.
2024-05-05 | GSE237512 | GEO
Project description:Background Neurofibromatosis type 1 (NF1) is a multi-organ disease caused by mutations in Neurofibromin (NF1). Amongst other features, NF1 patients frequently show reduced muscle mass and strength, impairing patients’ mobility and increasing the risk of fall. The role of Nf1 in muscle and the cause for the NF1-associated myopathy is mostly unknown. Methods To dissect the function of Nf1 in muscle, we created muscle-specific knockout mouse models for Nf1, inactivating Nf1 in the prenatal myogenic lineage either under the Lbx1 promoter or under the Myf5 promoter. Mice were analyzed during pre-and postnatal myogenesis and muscle growth. Results Nf1Lbx1 and Nf1Myf5 animals showed only mild defects in prenatal myogenesis. Nf1Lbx1 animals were perinatally lethal, while Nf1Myf5 animals survived up to approx. 25 weeks. Nf1Myf5 animals showed decreased postnatal growth, reduced muscle size, and fast fiber atrophy. Proteome and transcriptome analysis of muscle tissue indicated decreased protein synthesis and increased proteasomal degradation, and decreased glycolytic and increased oxidative activity in muscle tissue. Real-time respirometry demonstrated enhanced oxidative metabolism in Nf1Myf5 muscles concomitant to a fiber type shift from type 2B to type 2A and type 1. Nf1Myf5 muscles showed hallmarks of mild oxidative stress and increased activation of AMPK indicating an energy deficit, increased expression of atrogenes and decreased activation of mTORC1. Proteome and transcriptome analysis indicated that oxidative fibers mainly relied on fatty acid catabolism. Inline, Nf1Myf5 animals showed a drastic reduction of white, but not brown, adipose tissue. Conclusions Our results demonstrate a cell-autonomous role for Nf1 in myogenic cells during postnatal muscle growth required for metabolic and proteostatic homeostasis. Furthermore, Nf1 deficiency in muscle leads to cross-tissue communication and mobilization of lipid reserves.
2020-10-26 | PXD017958 | Pride
Project description:Breast cancer is the most prevalent cancer in women, and most cases are believed to have a sporadic, rather than heritable basis. Therefore, a major challenge in cancer research is to determine the underlying genomic alterations leading to carcinogenesis and malignancy, and then use this information for personalized therapies. Genomic studies of human cancers that aim to identify causative mutations are complicated by the prevalence of passenger mutations, genetic heterogeneity, and the diversity of breast cancer etiologies and tumor subtypes. Mouse cancer models are powerful for untangling the genomic basis of cancers because genetic and phenotypic variation can be eliminated or controlled. To identify genes contributing to mammary tumorigenesis, we exploited the C3H-Mcm4Chaos3/Chaos3 (“Chaos3”) mouse model that, by virtue of bearing a defective DNA replicative helicase subunit that causes elevated genomic instability (GIN), sustains somatic alterations ultimately causing mammary adenocarcinomas. Genomic analysis of Chaos3 mammary tumors revealed recurrent copy number alterations (CNAs) of specific genomic regions, most notably deletion of the Neurofibromin 1 (Nf1) tumor suppressor gene in all cases. NF1, a negative regulator of RAS, is traditionally recognized for its role in driving the development of neurofibromas in the context of the human disease Neurofibromitosis but not breast cancer. We observed elevated RAS activation and increased sensitivity of both Chaos3 and human Nf1-mutated breast cancer lines to MAPK and/or PI3K/AKT pathway inhibitors. We also found striking overlap between Chaos3 CNAs and human breast cancer CNA data curated in public genomic databases, including Nf1 deletion. Together, our results indicate that spontaneous NF1 loss can drive breast cancer and suggests a potential therapeutic strategy in that subset of patients. reference x sample
2012-08-21 | E-GEOD-36240 | biostudies-arrayexpress
Project description:Phosphoinositide-3-kinase (PI3K)-α inhibitors are clinically active in squamous carcinoma (SCC) of the head and neck (H&N) bearing mutations or amplification of PIK3CA. We aimed to identify potential mechanism of resistance and have observed that SCCs cells overcome the antitumor effects of the PI3Kα inhibitor BYL719 by maintaining PI3K-independent activation of the mammalian target of rapamycin (mTOR). The persistent mTOR activation is mediated by the tyrosine kinase receptor AXL. We found that AXL is overexpressed in resistant tumors, dimerizes with the epidermal growth factor receptor (EGFR), phosphorylates EGFR tyrosine 1173, resulting in activation of phospholipase Cγ (PLCγ)- protein kinase C (PKC) that, in turn, activates mTOR. Finally, simultaneous treatment with PI3Kα and either EGFR, AXL or PKC inhibitors reverts this resistance. RNAseq from acquired resistant cells CAL33B, K180B were compared to their parental counterpart CAL33 and K180, respectively. K180 is a shortcut of KYSE180, and B stands for BYL719. Duplicate of parental sensitive cells and K180B, and triplicate for CAL33B.
2015-04-12 | E-GEOD-61515 | biostudies-arrayexpress