NETWORK TOXICOLOGY FOR THE CARDIOVASCULAR TOXICITY ANALYSIS OF TYROSINE KINASE INHIBITORS

Abstract

Objective: This study aims to explore potential molecular mechanisms and targets of cardiovascular toxicities caused by tyrosine kinase inhibitors. Therefore, toxicogenomic data mining was conducted focusing on sunitinib, sorafenib, pazopanib, axitinib, and their associations with cardiovascular diseases. Material and Method: Common genes between tyrosine kinase inhibitors and cardiovascular diseases were uncovered via comparative toxicogenomic databases. Additionally, protein-protein and gene-gene interactions were identified using STRING and GeneMANIA, respectively. Subsequently, hub proteins associated with tyrosine kinase inhibitor-induced cardiovascular diseases were determined through Metascape. Transcription factors and microRNAs related to this toxicity were identified using ChEA3 and MIENTURNET, respectively. Finally, gene ontology enrichment analysis and the most associated molecular pathways were identified using the DAVID database and Metascape, respectively. Result and Discussion: Toxicogenomic data mining revealed six genes common between tyrosine kinase inhibitors and cardiovascular diseases, with five of these genes (FLT1, FLT4, KDR, MAPK1, and MAPK3) identified as hub genes. Physical interaction was dominant among these hub genes (77.64%). Sunitinib, sorafenib, pazopanib, and axitinib generally downregulated the activities of these proteins. SOX17 and SOX18 were prominent among transcription factors, while hsa-miR-199a-3p was the most important microRNA associated with this toxicity. Moreover, the Ras signaling pathway was mostly associated with tyrosine kinase inhibitor-induced cardiovascular toxicities. These findings make a substantial contribution to understanding the processes underlying cardiovascular diseases induced by sunitinib, sorafenib, pazopanib, and axitinib. They also reveal novel potential therapeutic targets, including genes, proteins, transcription factors, microRNAs, and pathways.