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

Timothy J. Stuhlmiller, Jon S. Zawistowski, Xin Chen, Noah Sciaky, Steven P. Angus, Sean T. Hicks, Traci L. Parry, Wei Huang, Ju Youn Beak, Monte Willis, Gary L. Johnson, Brian C. Jensen

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 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. 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.

Original languageEnglish (US)
Article numbere006635
JournalJournal of the American Heart Association
Volume6
Issue number10
DOIs
StatePublished - Oct 1 2017
Externally publishedYes

Fingerprint

Gene Expression Profiling
Transducers
Epidermal Growth Factor Receptor
Phosphotransferases
Cardiac Myocytes
STAT3 Transcription Factor
Neoplasms
sorafenib
Cardiotoxicity
sunitinib
Erlotinib Hydrochloride
Transcriptome
Mass Spectrometry
Up-Regulation
Fatty Acids
Therapeutics
Pharmaceutical Preparations

Keywords

  • Antineoplastic agents
  • Cardiomyopathy
  • Cardiotoxicity
  • Protein kinase inhibitors
  • Proteomics

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

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. / Stuhlmiller, Timothy J.; Zawistowski, Jon S.; Chen, Xin; Sciaky, Noah; Angus, Steven P.; Hicks, Sean T.; Parry, Traci L.; Huang, Wei; Beak, Ju Youn; Willis, Monte; Johnson, Gary L.; Jensen, Brian C.

In: Journal of the American Heart Association, Vol. 6, No. 10, e006635, 01.10.2017.

Research output: Contribution to journalArticle

Stuhlmiller, Timothy J. ; Zawistowski, Jon S. ; Chen, Xin ; Sciaky, Noah ; Angus, Steven P. ; Hicks, Sean T. ; Parry, Traci L. ; Huang, Wei ; Beak, Ju Youn ; Willis, Monte ; Johnson, Gary L. ; Jensen, Brian C. / 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. In: Journal of the American Heart Association. 2017 ; Vol. 6, No. 10.
@article{329f3808dd854faaa9273c58c7df72fa,
title = "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",
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 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. 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.",
keywords = "Antineoplastic agents, Cardiomyopathy, Cardiotoxicity, Protein kinase inhibitors, Proteomics",
author = "Stuhlmiller, {Timothy J.} and Zawistowski, {Jon S.} and Xin Chen and Noah Sciaky and Angus, {Steven P.} and Hicks, {Sean T.} and Parry, {Traci L.} and Wei Huang and Beak, {Ju Youn} and Monte Willis and Johnson, {Gary L.} and Jensen, {Brian C.}",
year = "2017",
month = "10",
day = "1",
doi = "10.1161/JAHA.117.006635",
language = "English (US)",
volume = "6",
journal = "Journal of the American Heart Association",
issn = "2047-9980",
publisher = "Wiley-Blackwell",
number = "10",

}

TY - JOUR

T1 - 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

AU - Stuhlmiller, Timothy J.

AU - Zawistowski, Jon S.

AU - Chen, Xin

AU - Sciaky, Noah

AU - Angus, Steven P.

AU - Hicks, Sean T.

AU - Parry, Traci L.

AU - Huang, Wei

AU - Beak, Ju Youn

AU - Willis, Monte

AU - Johnson, Gary L.

AU - Jensen, Brian C.

PY - 2017/10/1

Y1 - 2017/10/1

N2 - 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 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. 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.

AB - 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 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. 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.

KW - Antineoplastic agents

KW - Cardiomyopathy

KW - Cardiotoxicity

KW - Protein kinase inhibitors

KW - Proteomics

UR - http://www.scopus.com/inward/record.url?scp=85032178155&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85032178155&partnerID=8YFLogxK

U2 - 10.1161/JAHA.117.006635

DO - 10.1161/JAHA.117.006635

M3 - Article

C2 - 29051215

AN - SCOPUS:85032178155

VL - 6

JO - Journal of the American Heart Association

JF - Journal of the American Heart Association

SN - 2047-9980

IS - 10

M1 - e006635

ER -