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Combinatorial Therapeutic Discovery Using Perturbational Gene-Expression Signatures

62 Pages Posted: 25 Oct 2018 Sneak Peek Status: Published

See all articles by Chen-Tsung Huang

Chen-Tsung Huang

National Taiwan University - Graduate Institute of Biomedical Electronics and Bioinformatics

Chiao-Hui Hsieh

National Taiwan University - Institute of Molecular and Cellular Biology

Yun-Hsien Chung

National Taiwan University - Department of Life Science

Yen-Jen Oyang

National Taiwan University - Graduate Institute of Biomedical Electronics and Bioinformatics

Hsuan-Cheng Huang

National Yang-Ming University - Institute of Biomedical Informatics

Hsueh-Fen Juan

National Taiwan University - Graduate Institute of Biomedical Electronics and Bioinformatics; National Taiwan University - Institute of Molecular and Cellular Biology; National Taiwan University - Department of Life Science; National Yang-Ming University - Institute of Biomedical Informatics

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Abstract

Cancer is a complex disease that relies on both oncogenic mutations and non-mutated genes for survival, thereafter 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 geneexpression- 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, reproducible in external datasets, and correlated with small-molecule sensitivity. Using this new approach, we predicted synergistic drug pairs for cancer, including most frequently the combinations of a topoisomerase inhibitor and an mTOR or PI3K inhibitor. We also experimentally confirmed the synergistic effects of one combination of CD-437 (a retinoid) and sirolimus (an mTOR inhibitor) and the other combination of narciclasine (a protein synthesis inhibitor) and purvalanol A (a CDK inhibitor) in two breast and two lung cancer cell lines. Our results corroborate a gene-expression-based strategy for combinatorial drug screening as a way to target non-mutated genes in complex diseases.

Suggested Citation

Huang, Chen-Tsung and Hsieh, Chiao-Hui and Chung, Yun-Hsien and Oyang, Yen-Jen and Huang, Hsuan-Cheng and Juan, Hsueh-Fen, Combinatorial Therapeutic Discovery Using Perturbational Gene-Expression Signatures (October 24, 2018). Available at SSRN: https://ssrn.com/abstract=3272241 or http://dx.doi.org/10.2139/ssrn.3272241
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Chen-Tsung Huang

National Taiwan University - Graduate Institute of Biomedical Electronics and Bioinformatics

Taipei 106
Taiwan

Chiao-Hui Hsieh

National Taiwan University - Institute of Molecular and Cellular Biology

Taipei
Taiwan

Yun-Hsien Chung

National Taiwan University - Department of Life Science

Taipei
Taiwan

Yen-Jen Oyang

National Taiwan University - Graduate Institute of Biomedical Electronics and Bioinformatics

Taipei 106
Taiwan

Hsuan-Cheng Huang

National Yang-Ming University - Institute of Biomedical Informatics ( email )

Taiwan

Hsueh-Fen Juan (Contact Author)

National Taiwan University - Graduate Institute of Biomedical Electronics and Bioinformatics ( email )

Taipei 106
Taiwan

National Taiwan University - Institute of Molecular and Cellular Biology ( email )

Taipei
Taiwan

National Taiwan University - Department of Life Science ( email )

Taipei
Taiwan

National Yang-Ming University - Institute of Biomedical Informatics ( email )

Taiwan

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