Cargando…

Transcriptomic profiling of human cardiac cells predicts protein kinase inhibitor-associated cardiotoxicity

Kinase inhibitors (KIs) represent an important class of anti-cancer drugs. Although cardiotoxicity is a serious adverse event associated with several KIs, the reasons remain poorly understood, and its prediction remains challenging. We obtain transcriptional profiles of human heart-derived primary c...

Descripción completa

Detalles Bibliográficos
Autores principales: van Hasselt, J. G. Coen, Rahman, Rayees, Hansen, Jens, Stern, Alan, Shim, Jaehee V., Xiong, Yuguang, Pickard, Amanda, Jayaraman, Gomathi, Hu, Bin, Mahajan, Milind, Gallo, James M., Goldfarb, Joseph, Sobie, Eric A., Birtwistle, Marc R., Schlessinger, Avner, Azeloglu, Evren U., Iyengar, Ravi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511315/
https://www.ncbi.nlm.nih.gov/pubmed/32968055
http://dx.doi.org/10.1038/s41467-020-18396-7
Descripción
Sumario:Kinase inhibitors (KIs) represent an important class of anti-cancer drugs. Although cardiotoxicity is a serious adverse event associated with several KIs, the reasons remain poorly understood, and its prediction remains challenging. We obtain transcriptional profiles of human heart-derived primary cardiomyocyte like cell lines treated with a panel of 26 FDA-approved KIs and classify their effects on subcellular pathways and processes. Individual cardiotoxicity patient reports for these KIs, obtained from the FDA Adverse Event Reporting System, are used to compute relative risk scores. These are then combined with the cell line-derived transcriptomic datasets through elastic net regression analysis to identify a gene signature that can predict risk of cardiotoxicity. We also identify relationships between cardiotoxicity risk and structural/binding profiles of individual KIs. We conclude that acute transcriptomic changes in cell-based assays combined with drug substructures are predictive of KI-induced cardiotoxicity risk, and that they can be informative for future drug discovery.