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Updated: Dec 3, 2025
A Multiplexed Luciferase-based Screening Platform for Interrogating Cancer-associated Signal Transduction in Cultured Cells
Published on: July 3, 2013
Integrating LINCS Data to Evaluate Cancer Transcriptome Modifying Potential of Small-molecule Compounds for Drug
Yachao Zhao1, Yang Liu2, Hui Bai3
1The Eighth Medical Center of PLA General Hospital, Beijing, China.
Background:
Conventional high-throughput chemical screens in conjunction with genome-wide gene expression profiling proves to be successful in novel anti-cancer agent discovery and provides comprehensive insights into the mechanisms of action and off-target effects of single small-molecule compound. However, systematic evaluation on heterogeneous transcriptional responses of different cancer cell types to thousands of independent perturbations in a bioinformatics way is still limited.
Method:
Here, we introduce cancer transcriptome modifying potential (CTMP) which uses "Connectivity Score" to quantify and compare the effects of approved antineoplastic drugs on transcriptionally restoring dysregulated (both up- and down-) gene expressions at cancer state towards normal state. As a proof-of-concept, we applied this CTMP computational evaluation on > 10,000 small-molecule compounds using >200,000 Library of Integrated Network-based Cellular Signatures (LINCS) expression profiles generated upon 4 different cancer cell lines. We screened and proposed a candidate list of cancer transcriptome modifying therapeutics (CTMTs), among which the approved on-market drugs are further validated using GDSC drug sensitivity data, highlighting their potential to facilitate direct antineoplastic repositioning.
Results:
In total, we calculated CTMPs of 85 on-market antineoplastic drugs and ~15,000 smallmolecule compounds using 253,813 transcriptomes across four cancer cell lines of lung, melanoma, prostate, and colon. Our results reveal that regardless of the chemical structure and targeted proteins majority of approved antineoplastic drugs present significant bilateral CTMPs across all 4 cancer cell lines. Bilateral CTMP-based systematic screen further indicates that candidate CTMTs are limited and most notably cancer-type specific. In particular, for each cancer cell type we proposed 3~5 CTMTs that are approved drugs with potent sensitivity data to support development in antineoplastic indications.
Conclusion:
Our work establishes CTMP to evaluate the antineoplastic property of small-molecule compounds and suggests CTMP-based systematic screen of cancer type-specific CTMTs as a feasible strategy in drug repositioning for precise anti-cancer purposes.
Insights
This study introduces a new method, cancer transcriptome modifying potential (CTMP), to evaluate anti-cancer drug effects on gene expression. It identifies specific cancer transcriptome modifying therapeutics (CTMTs) for targeted drug repositioning in cancer treatment.
Area of Science:
- Computational biology
- Pharmacogenomics
- Drug discovery
Background:
- High-throughput screening and gene expression profiling aid anti-cancer drug discovery.
- Systematic bioinformatics evaluation of heterogeneous cancer cell responses to perturbations remains limited.
Purpose of the Study:
- Introduce cancer transcriptome modifying potential (CTMP) to quantify drug effects on gene expression.
- Develop a computational strategy for identifying novel anti-cancer therapeutics through drug repositioning.
Main Methods:
- Applied CTMP and Connectivity Score to >10,000 compounds using >200,000 LINCS expression profiles across 4 cancer cell lines.
- Validated promising candidates, particularly approved drugs, using GDSC drug sensitivity data.
Main Results:
- Calculated CTMPs for 85 approved antineoplastic drugs and ~15,000 compounds across lung, melanoma, prostate, and colon cancer cell lines.
- Identified significant bilateral CTMPs for most approved drugs, with candidate CTMTs being cancer-type specific.
- Proposed 3-5 approved drug CTMTs per cancer type with supporting sensitivity data.
Conclusions:
- CTMP provides a robust method for evaluating antineoplastic properties of small molecules.
- CTMP-based screening offers a feasible strategy for cancer-type-specific drug repositioning for precise anti-cancer therapies.
