https://scholars.lib.ntu.edu.tw/handle/123456789/452348
標題: | Perturbational Gene-Expression Signatures for Combinatorial Drug Discovery | 作者: | Huang C.-T. Hsieh C.-H. Chung Y.-H. Oyang Y.-J. Huang H.-C. Hsueh-Fen Juan |
公開日期: | 2019 | 出版社: | Elsevier B.V. | 卷: | 15 | 起(迄)頁: | 291-306 | 來源出版物: | iScience | 摘要: | Bioinformatics; Cancer Systems Biology; Pharmacoinformatics ? 2019 The Author(s)Cancer is a complex disease that relies on both oncogenic mutations and non-mutated genes for survival, and therefore coined as oncogene and non-oncogene addictions. The need for more effective combination therapies to overcome drug resistance in oncology has been increasingly recognized, but the identification of potentially synergistic drugs at scale remains challenging. Here we propose a gene-expression-based approach, which uses the recurrent perturbation-transcript regulatory relationships inferred from a large compendium of chemical and genetic perturbation experiments across multiple cell lines, to engender a testable hypothesis for combination therapies. These transcript-level recurrences were distinct from known compound-protein target counterparts, were reproducible in external datasets, and correlated with small-molecule sensitivity. We applied these recurrent relationships to predict synergistic drug pairs for cancer and experimentally confirmed two unexpected drug combinations in vitro. Our results corroborate a gene-expression-based strategy for combinatorial drug screening as a way to target non-mutated genes in complex diseases. ? 2019 The Author(s) |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/452348 | ISSN: | 25890042 | DOI: | 10.1016/j.isci.2019.04.039 |
顯示於: | 分子與細胞生物學研究所 |
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