A survey of optimal strategy for signature-based drug repositioning and an application to liver cancer

Abstract
Data availability
Article and author information
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Abstract

Pharmacologic perturbation projects, such as Connectivity Map (CMap) and Library of Integrated Network-based Cellular Signatures (LINCS), have produced many perturbed expression data, providing enormous opportunities for computational therapeutic discovery. However, there is no consensus on which methodologies and parameters are the most optimal to conduct such analysis. Aiming to fill this gap, new benchmarking standards were developed to quantitatively evaluate drug retrieval performance. Investigations of potential factors influencing drug retrieval were conducted based on these standards. As a result, we determined an optimal approach for LINCS data-based therapeutic discovery. With this approach, homoharringtonine (HHT) was identified to be a candidate agent with potential therapeutic and preventive effects on liver cancer. The antitumor and antifibrotic activity of HHT was validated experimentally using subcutaneous xenograft tumor model and carbon tetrachloride (CCL₄)-induced liver fibrosis model, demonstrating the reliability of the prediction results. In summary, our findings will not only impact the future applications of LINCS data but also offer new opportunities for therapeutic intervention of liver cancer.

Data availability

Sequencing data have been deposited in GEO under accession codes GSE180243 and GSE193897.All data generated or analysed during this study are included in the manuscript and supporting files.

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Article and author information

Author details

Chen Yang

Department of Liver Surgery, Shanghai Jiao Tong University, Shanghai, China

Competing interests
The authors declare that no competing interests exist.
Hailin Zhang

Department of Liver Surgery, Shanghai Jiao Tong University, Shanghai, China

Competing interests
The authors declare that no competing interests exist.
Mengnuo Chen

Department of Liver Surgery, Shanghai Jiao Tong University, Shanghai, China

Competing interests
The authors declare that no competing interests exist.
Siying Wang

Department of Liver Surgery, Shanghai Jiao Tong University, Shanghai, China

Competing interests
The authors declare that no competing interests exist.
Ruolan Qian

Department of Liver Surgery, Shanghai Jiao Tong University, Shanghai, China

Competing interests
The authors declare that no competing interests exist.
Linmeng Zhang

Department of Liver Surgery, Shanghai Jiao Tong University, Shanghai, China

Competing interests
The authors declare that no competing interests exist.
Xiaowen Huang

Division of Gastroenterology and Hepatology, Shanghai Jiao Tong University, Shanghai, China

Competing interests
The authors declare that no competing interests exist.
Jun Wang

Department of Liver Surgery, Shanghai Jiao Tong University, Shanghai, China

Competing interests
The authors declare that no competing interests exist.
Zhicheng Liu

Hepatic Surgery Center, Huazhong University of Science and Technology, Wuhan, China

Competing interests
The authors declare that no competing interests exist.
Wenxin Qin

Department of Liver Surgery, Shanghai Jiao Tong University, Shanghai, China

Competing interests
The authors declare that no competing interests exist.
Cun Wang

Department of Liver Surgery, Shanghai Jiao Tong University, Shanghai, China

For correspondence
cwang@shsci.org

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-4977-2189
Hualian Hang

Department of Liver Surgery, Shanghai Jiao Tong University, Shanghai, China

For correspondence
hanghualian@shsmu.edu.cn

Competing interests
The authors declare that no competing interests exist.
Hui Wang

Department of Liver Surgery, Shanghai Jiao Tong University, Shanghai, China

For correspondence
hwang@shsci.org

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-4947-9537

Funding

National Natural Science Foundation of China (81972208)

Hui Wang

National Natural Science Foundation of China (82170646)

Hualian Hang

Shanghai Natural Science Foundation (19ZR1452700)

Hui Wang

The Interdisciplinary Program of Shanghai Jiao Tong University (YG2021ZD10)

Hualian Hang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animals were manipulated according to protocols approved by the Shanghai Medical Experimental Animal Care Commission and Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.