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.