| アブストラクト | 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. |
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| 投稿者 | 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 |
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| 組織名 | Department of Pharmacological Sciences and Systems Biology Center New York, Icahn;School of Medicine at Mount Sinai, New York, NY, USA.;Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug;Research, Leiden University, Leiden, Netherlands.;Department of Genetics and Genomic Sciences, and Icahn Institute for Genomic;Sciences and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New;York, NY, USA.;Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical;Sciences, University at Buffalo, Buffalo, NY, USA.;Department of Chemical and Biomolecular Engineering, Clemson University, Clemson,;SC, USA.;avner.schlessinger@mssm.edu.;School of Medicine at Mount Sinai, New York, NY, USA. evren.azeloglu@mssm.edu.;Deparment of Medicine, Division of Nephrology, Icahn School of Medicine at Mount;Sinai, New York, NY, USA. evren.azeloglu@mssm.edu.;School of Medicine at Mount Sinai, New York, NY, USA. ravi.iyengar@mssm.edu. |
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