Integrative Cross-platform Analysis of Kinase Inhibitor Effects on Statin-relevant Cardioprotective Pathways in Human Cardiomyocytes.

Abstract

BACKGROUND/AIM: Kinase inhibitors (KIs) can cause cardiotoxicity through mechanisms overlapping with statin cardioprotective pathways, yet their effects on these pathways in cardiomyocytes remain uncertain. We evaluated six literature-defined statin-relevant gene sets using transcriptomic and proteomic data. MATERIALS AND METHODS: Pre-ranked gene set enrichment analysis was performed for 23 KIs in primary cardiac cells (GSE146096; n=319) and iPSC-derived cardiomyocytes (GSE217421; n=541), with cross-platform analysis of 21 KIs by shotgun proteomics (PXD014791; n=300). Pathway-specific concordance was assessed by Spearman correlation with Benjamini-Hochberg correction; protein scores were estimated after adjustment for cell line. RESULTS: KI effects were heterogeneous. The anti-fibrotic pathway showed nominal concordance across the two transcriptomic datasets (ρ=0.495, p=0.016, q=0.098; 91% direction concordance) and significant cell-line-adjusted transcriptomic-proteomic concordance (ρ=0.644, p=0.0016, q=0.0081). Nilotinib reproducibly upregulated NF-κB pathway genes [normalized enrichment score (NES)=+2.29 and +2.18 in discovery and validation], with targeted inter-gene-correlation-adjusted testing supporting higher NF-κB expression than under rosuvastatin (CAMERA p=3.54×10-8). No global cross-omics summary remained significant after harmonizing pathway universes and accounting for repeated pathways. CONCLUSION: KI effects on statin-relevant pathways were pathway-specific. Anti-fibrotic concordance and nilotinib-associated NF-κB upregulation are hypothesis-generating candidates for experimental validation.