Transcriptomic signatures for cardiotoxicity of kinase inhibitor cancer drugs in human myocytes

抄録

The Drug Toxicity Signature Generation Center (DtoxS.org), is a NIH funded center to obtain cellular signatures for toxicity associated with therapeutic agents. Adverse events involving diminished cardiac contractility leading to heart failure is associated with efficacious protein kinase inhibitors used to treat various cancers. My colleagues and I in this center have sought to develop clinically-weighted transcriptomic signatures to predict risk of kinase inhibitor drug induced cardiotoxicity and to better understand the biological processes associated with risk of cardiotoxicity. We obtained transcriptome-wide response profiles in human primary cardiomyocyte like cell lines and healthy human subject iPSC derived myocytes that were treated with twenty two different FDA approved kinase inhibitor drugs. The FDA Adverse Event Reporting System was used to derive risk scores for these drugs for different types of cardiotoxicity. We used elastic net regression to associate these transcriptomic profiles with kinase inhibitor-associated risk scores for cardiac disease subtypes to obtain clinically-weighted transcriptomic signatures, which showed good predictive properties: the signature could predict relative cardiotoxicity risk for two kinase inhibitors not included in the analysis. The gene products in the signatures form closely connected protein-protein interaction networks. Multidimensional analyses indicate structural features of these drugs could also be selectively associated transcriptomic signatures and clinical risk. These studies indicate that transcriptomic signatures can be useful early predictors of adverse events during drug development.

We remember the crucial role Darrell Abernethy played in promoting the science of predictive toxicology and dedicate these studies to his memory.