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      Pharmacogenomic synthetic lethal screens reveal hidden vulnerabilities and new therapeutic approaches for treatment of NF1-associated tumors

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          Abstract

          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.

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          Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2

          In comparative high-throughput sequencing assays, a fundamental task is the analysis of count data, such as read counts per gene in RNA-seq, for evidence of systematic changes across experimental conditions. Small replicate numbers, discreteness, large dynamic range and the presence of outliers require a suitable statistical approach. We present DESeq2, a method for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates. This enables a more quantitative analysis focused on the strength rather than the mere presence of differential expression. The DESeq2 package is available at http://www.bioconductor.org/packages/release/bioc/html/DESeq2.html. Electronic supplementary material The online version of this article (doi:10.1186/s13059-014-0550-8) contains supplementary material, which is available to authorized users.
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            Trimmomatic: a flexible trimmer for Illumina sequence data

            Motivation: Although many next-generation sequencing (NGS) read preprocessing tools already existed, we could not find any tool or combination of tools that met our requirements in terms of flexibility, correct handling of paired-end data and high performance. We have developed Trimmomatic as a more flexible and efficient preprocessing tool, which could correctly handle paired-end data. Results: The value of NGS read preprocessing is demonstrated for both reference-based and reference-free tasks. Trimmomatic is shown to produce output that is at least competitive with, and in many cases superior to, that produced by other tools, in all scenarios tested. Availability and implementation: Trimmomatic is licensed under GPL V3. It is cross-platform (Java 1.5+ required) and available at http://www.usadellab.org/cms/index.php?page=trimmomatic Contact: usadel@bio1.rwth-aachen.de Supplementary information: Supplementary data are available at Bioinformatics online.
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                Author and article information

                Journal
                bioRxiv
                BIORXIV
                bioRxiv
                Cold Spring Harbor Laboratory
                25 March 2024
                : 2024.03.25.585959
                Affiliations
                [1 ]Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
                [2 ]Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital, Cincinnati, OH, 45229, USA.
                [3 ]Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA.
                Author notes

                Authorship statement: Designed the study: K.B.W., D.A.L. Advised the study: A.T.L., B.J.K., T.J., N.R., C.L.M., D.A.L. Acquired funding: D.A.L, N.R., K.B.W. Acquired and generated cell lines: K.B.W, A.T.L., R.L.W. Performed experiments and analyzed data: K.B.W., B.J.K., A.T.L., K.E.C., R.L.W. Performed bioinformatic and statistical analysis: T.J., S.K.R. Wrote the manuscript: K.B.W.

                Corresponding author: Kyle Williams, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA ( kbwillia@ 123456umn.edu )
                Author information
                http://orcid.org/0000-0003-4333-9111
                http://orcid.org/0000-0002-1350-8271
                http://orcid.org/0000-0002-2849-1572
                http://orcid.org/0000-0002-4972-8233
                http://orcid.org/0009-0003-9578-4847
                http://orcid.org/0000-0002-5474-588X
                http://orcid.org/0000-0001-5030-9354
                http://orcid.org/0000-0002-3183-0491
                Article
                10.1101/2024.03.25.585959
                10996510
                38585724
                fb4da5a5-bc97-4f92-bb5f-15d28907e843

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.

                History
                Funding
                This work was funded in part by grants to D.A.L. including the American Cancer Society Research Professor Award (#123939), National Institute on Neurological Disease and Stroke (R01NS115438), National Cancer Institute (R01NS086219), the Pre-Clinical Research Award Neurofibromatosis Research Initiative (NFRI) through Boston Children’s Hospital (GENFD0001769008), and the Drug Discovery Initiative Award and Synodos for NF1 Award from the Children’s Tumor Foundation.
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