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Perturbational Gene-Expression Signatures for Combinatorial Drug Discovery

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 id...

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Autores principales: Huang, Chen-Tsung, Hsieh, Chiao-Hui, Chung, Yun-Hsien, Oyang, Yen-Jen, Huang, Hsuan-Cheng, Juan, Hsueh-Fen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525321/
https://www.ncbi.nlm.nih.gov/pubmed/31102995
http://dx.doi.org/10.1016/j.isci.2019.04.039
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author Huang, Chen-Tsung
Hsieh, Chiao-Hui
Chung, Yun-Hsien
Oyang, Yen-Jen
Huang, Hsuan-Cheng
Juan, Hsueh-Fen
author_facet Huang, Chen-Tsung
Hsieh, Chiao-Hui
Chung, Yun-Hsien
Oyang, Yen-Jen
Huang, Hsuan-Cheng
Juan, Hsueh-Fen
author_sort Huang, Chen-Tsung
collection PubMed
description 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.
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spelling pubmed-65253212019-05-28 Perturbational Gene-Expression Signatures for Combinatorial Drug Discovery Huang, Chen-Tsung Hsieh, Chiao-Hui Chung, Yun-Hsien Oyang, Yen-Jen Huang, Hsuan-Cheng Juan, Hsueh-Fen iScience Article 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. Elsevier 2019-05-04 /pmc/articles/PMC6525321/ /pubmed/31102995 http://dx.doi.org/10.1016/j.isci.2019.04.039 Text en © 2019 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Huang, Chen-Tsung
Hsieh, Chiao-Hui
Chung, Yun-Hsien
Oyang, Yen-Jen
Huang, Hsuan-Cheng
Juan, Hsueh-Fen
Perturbational Gene-Expression Signatures for Combinatorial Drug Discovery
title Perturbational Gene-Expression Signatures for Combinatorial Drug Discovery
title_full Perturbational Gene-Expression Signatures for Combinatorial Drug Discovery
title_fullStr Perturbational Gene-Expression Signatures for Combinatorial Drug Discovery
title_full_unstemmed Perturbational Gene-Expression Signatures for Combinatorial Drug Discovery
title_short Perturbational Gene-Expression Signatures for Combinatorial Drug Discovery
title_sort perturbational gene-expression signatures for combinatorial drug discovery
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525321/
https://www.ncbi.nlm.nih.gov/pubmed/31102995
http://dx.doi.org/10.1016/j.isci.2019.04.039
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