Andre Neil Forbes, Duo Xu, Sandra Cohen, Priya Pancholi, Ekta Khurana
{"title":"利用染色质可及性和转录组数据发现癌症治疗靶点。","authors":"Andre Neil Forbes, Duo Xu, Sandra Cohen, Priya Pancholi, Ekta Khurana","doi":"10.1016/j.cels.2024.08.004","DOIUrl":null,"url":null,"abstract":"<p><p>Most cancer types lack targeted therapeutic options, and when first-line targeted therapies are available, treatment resistance is a huge challenge. Recent technological advances enable the use of assay for transposase-accessible chromatin with sequencing (ATAC-seq) and RNA sequencing (RNA-seq) on patient tissue in a high-throughput manner. Here, we present a computational approach that leverages these datasets to identify drug targets based on tumor lineage. We constructed gene regulatory networks for 371 patients of 22 cancer types using machine learning approaches trained with three-dimensional genomic data for enhancer-to-promoter contacts. Next, we identified the key transcription factors (TFs) in these networks, which are used to find therapeutic vulnerabilities, by direct targeting of either TFs or the proteins that they interact with. We validated four candidates identified for neuroendocrine, liver, and renal cancers, which have a dismal prognosis with current therapeutic options.</p>","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"824-837.e6"},"PeriodicalIF":0.0000,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11415227/pdf/","citationCount":"0","resultStr":"{\"title\":\"Discovery of therapeutic targets in cancer using chromatin accessibility and transcriptomic data.\",\"authors\":\"Andre Neil Forbes, Duo Xu, Sandra Cohen, Priya Pancholi, Ekta Khurana\",\"doi\":\"10.1016/j.cels.2024.08.004\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Most cancer types lack targeted therapeutic options, and when first-line targeted therapies are available, treatment resistance is a huge challenge. Recent technological advances enable the use of assay for transposase-accessible chromatin with sequencing (ATAC-seq) and RNA sequencing (RNA-seq) on patient tissue in a high-throughput manner. Here, we present a computational approach that leverages these datasets to identify drug targets based on tumor lineage. We constructed gene regulatory networks for 371 patients of 22 cancer types using machine learning approaches trained with three-dimensional genomic data for enhancer-to-promoter contacts. Next, we identified the key transcription factors (TFs) in these networks, which are used to find therapeutic vulnerabilities, by direct targeting of either TFs or the proteins that they interact with. We validated four candidates identified for neuroendocrine, liver, and renal cancers, which have a dismal prognosis with current therapeutic options.</p>\",\"PeriodicalId\":93929,\"journal\":{\"name\":\"Cell systems\",\"volume\":\" \",\"pages\":\"824-837.e6\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-09-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11415227/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell systems\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1016/j.cels.2024.08.004\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/9/4 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell systems","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.cels.2024.08.004","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/9/4 0:00:00","PubModel":"Epub","JCR":"","JCRName":"","Score":null,"Total":0}
Discovery of therapeutic targets in cancer using chromatin accessibility and transcriptomic data.
Most cancer types lack targeted therapeutic options, and when first-line targeted therapies are available, treatment resistance is a huge challenge. Recent technological advances enable the use of assay for transposase-accessible chromatin with sequencing (ATAC-seq) and RNA sequencing (RNA-seq) on patient tissue in a high-throughput manner. Here, we present a computational approach that leverages these datasets to identify drug targets based on tumor lineage. We constructed gene regulatory networks for 371 patients of 22 cancer types using machine learning approaches trained with three-dimensional genomic data for enhancer-to-promoter contacts. Next, we identified the key transcription factors (TFs) in these networks, which are used to find therapeutic vulnerabilities, by direct targeting of either TFs or the proteins that they interact with. We validated four candidates identified for neuroendocrine, liver, and renal cancers, which have a dismal prognosis with current therapeutic options.