Molecularly Guided Drug Repurposing for Cholangiocarcinoma: An Integrative Bioinformatic Approach.

Simran Venkatraman,Somchai Chutipongtanate,Pisut Pongchaikul,Brinda Balasubramanian,Rutaiwan Tohtong

doi:10.3390/genes13020271

Simran Venkatraman, Somchai Chutipongtanate + Show 3 more

Open Access

https://doi.org/10.3390/genes13020271

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Abstract

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.

Highlights

Cholangiocarcinoma (CCA) is a highly prevalent biliary malignancy that is notoriously heterogeneous and is usually diagnosed at advanced stages [1]
To identify which immune-related genes are associated with patient prognosis, the Cox Proportional Univariate regression model was applied to CCA patients of both cohorts, GSE107943 and TCGA-CHOL, assessing the effect of each gene in the list against the overall survival
The common 26 genes were significantly enriched in oncogenic pathways, e.g., TP53 network and PI3K/AKT/mTOR signaling (Figure S1b), that linked to CCA oncogenesis and chemoresistance [1]

Summary

Introduction

Cholangiocarcinoma (CCA) is a highly prevalent biliary malignancy that is notoriously heterogeneous and is usually diagnosed at advanced stages [1]. Cancer-associated fibroblasts, tumor-associated macrophages, myeloid-derived suppressor cells, stromal cells, and cytokines promote an immunosuppressive environment to foster CCA progression. Infiltration of these cells in CCA is associated with poor survival. Genes 2022, 13, 271 rived suppressor cells, stromal cells, and cytokines promote an immunosuppressive environment to foster CCA progression. Infiltration of these cells in CCA is associated with poouotcrosmurevsiv[2a,l3o].utDcoume etso[i2t,s3]m. Unsupervised clustering stratified CCA tumors into two groups according to the immune-oncogenic gene signature expression, which confirmed its clinical relevance by Kaplan–Meier curve. 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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