Journal
GENES
Volume 13, Issue 2, Pages -Publisher
MDPI
DOI: 10.3390/genes13020271
Keywords
cholangiocarcinoma; connectivity map; drug-gene network; drug repurposing; immuneoncogenic gene signature; transcriptomics; survival analysis
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Funding
- Mahidol University (Reinventing University Program)
- Office of Higher Education, Science, Research and Innovation Policy Council, Thailand [B05F630066]
- New Discovery and Frontier Research Grant of Mahidol University [NDFR19/2563]
- Genomic Thailand Project of the Health Systems Research Institute [HSRI64-130]
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This study utilized transcriptomic data and bioinformatic methods to repurpose FDA-approved drugs for cholangiocarcinoma (CCA) treatment, identifying high-risk patients through an immune-oncogenic gene signature and identifying 8 FDA-approved drugs as promising candidates for potential use in treatment.
Background: Cholangiocarcinoma (CCA) has a complex immune microenvironment architecture, thus possessing challenges in its characterization and treatment. This study aimed to repurpose FDA-approved drugs for cholangiocarcinoma by transcriptomic-driven bioinformatic approach. Methods: Cox-proportional univariate regression was applied to 3017 immune-related genes known a priori to identify a list of mortality-associated genes, so-called immune-oncogenic gene signature, in CCA tumor-derived RNA-seq profiles of two independent cohorts. Unsupervised clustering stratified CCA tumors into two groups according to the immune-oncogenic gene signature expression, which then confirmed its clinical relevance by Kaplan-Meier curve. Molecularly guided drug repurposing was performed by an integrative connectivity map-prioritized drug-gene network analysis. Results: The immune-oncogenic gene signature consists of 26 mortality-associated immune-related genes. Patients with high-expression signature had a poorer overall survival (log-rank p < 0.001), while gene enrichment analysis revealed cell-cycle checkpoint regulation and inflammatory-immune response signaling pathways affected this high-risk group. The integrative drug-gene network identified eight FDA-approved drugs as promising candidates, including Dasatinib a multi-kinase inhibitor currently investigated for advanced CCA with isocitrate-dehydrogenase mutations. Conclusion: This study proposes the use of the immune-oncogenic gene signature to identify high-risk CCA patients. Future preclinical and clinical studies are required to elucidate the therapeutic efficacy of the molecularly guided drugs as the adjunct therapy, aiming to improve the survival outcome.
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