RT Journal Article
SR Electronic
T1 Clinically-weighted transcriptomic signatures for protein kinase inhibitor associated cardiotoxicity
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 075754
DO 10.1101/075754
A1 JGC van Hasselt
A1 J Hansen
A1 Y Xiong
A1 J Shim
A1 A Pickard
A1 G Jayaraman
A1 B Hu
A1 M Mahajan
A1 J Gallo
A1 EA Sobie
A1 MR Birtwistle
A1 EU Azeloglu
A1 R Iyengar
YR 2016
UL http://biorxiv.org/content/early/2016/09/19/075754.abstract
AB Cardiotoxicity (CT) involving diminished cardiac contractility and heart failure is a major adverse event associated with otherwise efficacious protein kinase inhibitors (KIs). Here, we sought to develop clinically-weighted transcriptomic signatures to predict risk of CT and to better understand the biological processes associated with CT risk. We obtained transcriptome-wide response profiles in four human primary cardiomyocyte cell lines that were treated with 22 different KIs using mRNA sequencing with 3’ digital gene expression. The FDA Adverse Event Reporting System was used to derive relative risk scores for four types of CT for different KIs. We used elastic net regression to associate these transcriptomic profiles with KI-associated risk scores for CT subtypes to obtain clinically-weighted transcriptomic signatures, which showed good predictive properties (cross-validation R2 >0.87). Our clinically-weighted transcriptomic signatures for KI-associated CT may be of relevance in early drug development for the prediction of KI-associated CT.