Kinome and Transcriptome Profiling Reveal Broad and Distinct Activities of Erlotinib, Sunitinib, and Sorafenib in the Mouse Heart and Suggest Cardiotoxicity From Combined Signal Transducer and Activator of Transcription and Epidermal Growth Factor Receptor Inhibition

Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease

Traci L. Parry¹  Noah Sciaky²  Steven P. Angus²  Monte S. Willis²  Brian C. Jensen²  Gary L. Johnson²  Jon S. Zawistowski²  Xin Chen²  Timothy J. Stuhlmiller²  Ju Youn Beak³  Wei Huang³  Sean T. Hicks³ 

[1] Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, NC;Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC;University of North Carolina McAllister Heart Institute, Chapel Hill, NC;

关键词: antineoplastic agents;    cardiomyopathy;    cardiotoxicity;    protein kinase inhibitors;    proteomics;   

DOI  :  10.1161/JAHA.117.006635

来源: DOAJ

【 摘 要 】

BackgroundMost novel cancer therapeutics target kinases that are essential to tumor survival. Some of these kinase inhibitors are associated with cardiotoxicity, whereas others appear to be cardiosafe. The basis for this distinction is unclear, as are the molecular effects of kinase inhibitors in the heart. Methods and ResultsWe administered clinically relevant doses of sorafenib, sunitinib (cardiotoxic multitargeted kinase inhibitors), or erlotinib (a cardiosafe epidermal growth factor receptor inhibitor) to mice daily for 2 weeks. We then compared the effects of these 3 kinase inhibitors on the cardiac transcriptome using RNAseq and the cardiac kinome using multiplexed inhibitor beads coupled with mass spectrometry. We found unexpectedly broad molecular effects of all 3 kinase inhibitors, suggesting that target kinase selectivity does not define either the molecular response or the potential for cardiotoxicity. Using in vivo drug administration and primary cardiomyocyte culture, we also show that the cardiosafety of erlotinib treatment may result from upregulation of the cardioprotective signal transducer and activator of transcription 3 pathway, as co‐treatment with erlotinib and a signal transducer and activator of transcription inhibitor decreases cardiac contractile function and cardiomyocyte fatty acid oxidation. ConclusionsCollectively our findings indicate that preclinical kinome and transcriptome profiling may predict the cardiotoxicity of novel kinase inhibitors, and suggest caution for the proposed therapeutic strategy of combined signal transducer and activator of transcription/epidermal growth factor receptor inhibition for cancer treatment.

【 授权许可】

Unknown