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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
- Source :
- Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
- Publication Year :
- 2017
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2017.
-
Abstract
- Background Most 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 Results We 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 RNA seq 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. Conclusions Collectively 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.
- Subjects :
- Proteomics
0301 basic medicine
Indoles
Time Factors
Translational Studies
Molecular Cardiology
Rats, Sprague-Dawley
Mice
Mechanisms
Sunitinib
Myocytes, Cardiac
Kinome
Molecular Targeted Therapy
Protein Interaction Maps
Epidermal growth factor receptor
Erlotinib Hydrochloride
Cells, Cultured
Original Research
biology
Fatty Acids
Heart
Sorafenib
3. Good health
ErbB Receptors
Echocardiography
Female
Erlotinib
Signal transduction
Cardiology and Cardiovascular Medicine
Oxidation-Reduction
Signal Transduction
medicine.drug
Niacinamide
STAT3 Transcription Factor
Heart Diseases
cardiotoxicity
Antineoplastic Agents
03 medical and health sciences
medicine
Animals
Pyrroles
Protein Kinase Inhibitors
Cardiotoxicity
Dose-Response Relationship, Drug
business.industry
Gene Expression Profiling
Myocardium
Phenylurea Compounds
Myocardial Contraction
030104 developmental biology
Animal Models of Human Disease
Cancer research
biology.protein
business
cardiomyopathy
Basic Science Research
Subjects
Details
- ISSN :
- 20479980
- Volume :
- 6
- Database :
- OpenAIRE
- Journal :
- Journal of the American Heart Association
- Accession number :
- edsair.doi.dedup.....a0a2070a0da24cd1e09499477683b50c