Molecularly Guided Drug Repurposing for Cholangiocarcinoma: An Integrative Bioinformatic Approach
Issued Date
2022-02-01
Resource Type
eISSN
20734425
Scopus ID
2-s2.0-85124107727
Pubmed ID
35205315
Journal Title
Genes
Volume
13
Issue
2
Rights Holder(s)
SCOPUS
Bibliographic Citation
Genes Vol.13 No.2 (2022)
Suggested Citation
Venkatraman S., Balasubramanian B., Pongchaikul P., Tohtong R., Chutipongtanate S. Molecularly Guided Drug Repurposing for Cholangiocarcinoma: An Integrative Bioinformatic Approach. Genes Vol.13 No.2 (2022). doi:10.3390/genes13020271 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/83839
Title
Molecularly Guided Drug Repurposing for Cholangiocarcinoma: An Integrative Bioinformatic Approach
Other Contributor(s)
Abstract
Background: Cholangiocarcinoma (CCA) has a complex immune microenvironment archi-tecture, thus possessing challenges in its characterization and treatment. This study aimed to repur-pose 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.