[SOT 2017] Phenotypic Profiling in Human Primary Cell-Based Systems Provides Mechanistic Insight into the Cardiotoxicity of Tyrosine Kinase Inhibitors

[SOT 2017] Phenotypic Profiling in Human Primary Cell-Based Systems Provides Mechanistic Insight into the Cardiotoxicity of Tyrosine Kinase Inhibitors
Version:
20719

File Name/Number:
2017 Society of Toxicology

Year:
2017

Rationale: Tyrosine kinase inhibitors used for oncology indications are associated with cardiovascular toxicity and patients taking the allosteric MEK inhibitor, trametinib, develop evidence of cardiomyopathy. We find that trametinib is active across a panel of human
primary cell-based tissue and disease models that include cell models relevant to vascular dysfunction. Our goal was to determine if analysis of the activities of trametinib would provide insight into potential mechanisms of toxicity.

Method: The activities of trametinib in this panel were evaluated for relevance to cardiovascular disease mechanisms. One highly relevant biomarker activity found was increased cell surface levels of serum amyloid a (SAA) in a human primary cell-based model of vascular inflammation, consisting of coronary artery smooth muscle cells (the BioMAP CASM3C system), stimulated with a cocktail of proinflammatory cytokines. SAA is an apolipoprotein family member and acute phase response protein that is a clinical risk factor for cardiovascular disease. To further characterize the association of increased SAA with potential for cardiotoxicity, we analyzed a large reference dataset, containing more than 4,500 test agents (drugs, experimental chemicals, etc.). This database was searched to identify agents that increase levels of SAA in the BioMAP CASM3C system relative to vehicle control and to assess any association with cardiotoxicity.

Results: Fewer than 2% of profiles in the database were found to increase SAA in the BioMAP CASM3C system. In addition to MEK inhibitors, including the dual Raf/MEK inhibitor RO-5126766, we identified several other TKIs (Bosutinib, R428, and nintedanib), corticosteroids,
aldosterone, HDAC inhibitors, IL-6 Pathway agonists, sirtuins, modulators of mitochondrial function, as well as nicotine and several industrial chemicals increased the levels of SAA at two or more concentrations.

Conclusions: Here we describe an in vitro signature, increased SAA in a coronary artery smooth muscle cell model of vascular inflammation, shared by certain compound classes associated with cardiovascular toxicity. These data suggest that one mechanism by which MEK inhibitors, HDAC inhibitors, GR Agonists, and IL-6 pathway agonists contribute to cardiovascular toxicity is by direct promotion of vascular dysfunction through SAA within vascular tissues. These mechanistic insights, connecting targets to clinical outcomes through specific biological processes, may be helpful for developing and testing adverse outcome pathways for cardiovascular toxicity.