Transcriptomic profiling of human cardiac cells predicts protein kinase inhibitor-associated cardiotoxicity

Hasselt, J. G. Coen van; Rahman, Rayees; Hansen, Jens; Stern, Ari; Shim, Jaehee; Xiong, Yuguang; Pickard, Amanda J.; Jayaraman, Gomathi; Hu, Bin; Mahajan, Milind; Gallo, James M.; Goldfarb, Joseph; Sobie, Eric A.; Birtwistle, Marc R.; Schlessinger, Avner; Azeloglu, Evren U.; Iyengar, Ravi

doi:10.1038/s41467-020-18396-7

Cited by 32 publications

(26 citation statements)

References 41 publications

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“…Despite being clinically efficacious, ponatinib has been associated with a high rate of cardiovascular adverse events, with a recent retrospective study finding 5% of patients with HF and more than 20% to experience an adverse cardiovascular event with ponatinib therapy [ 68 ]. Analysis of the FDA adverse event reporting system database has found ponatinib to carry the greatest risk of cardiotoxicity amongst all kinase inhibitors [ 69 ], with disproportionally high reporting of cardiac failure, ischaemic heart disease and hypertension compared to other anticancer therapies for CML [ 70 ].…”

Section: Metabolic Dysfunction Leading To Cardiotoxicity Of Specific Chemotherapiesmentioning

confidence: 99%

Cancer Therapy-Induced Cardiotoxicity—A Metabolic Perspective on Pathogenesis, Diagnosis and Therapy

Choksey

Timm

2021

IJMS

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Long-term cardiovascular complications of cancer therapy are becoming ever more prevalent due to increased numbers of cancer survivors. Cancer therapy-induced cardiotoxicity (CTIC) is an incompletely understood consequence of various chemotherapies, targeted anti-cancer agents and radiation therapy. It is typically detected clinically by a reduction in cardiac left ventricular ejection fraction, assessed by echocardiography. However, once cardiac functional decline is apparent, this indicates irreversible cardiac damage, highlighting a need for the development of diagnostics which can detect CTIC prior to the onset of functional decline. There is increasing evidence to suggest that pathological alterations to cardiac metabolism play a crucial role in the development of CTIC. This review discusses the metabolic alterations and mechanisms which occur in the development of CTIC, with a focus on doxorubicin, trastuzumab, imatinib, ponatinib, sunitinib and radiotherapy. Potential methods to diagnose and predict CTIC prior to functional cardiac decline in the clinic are evaluated, with a view to both biomarker and imaging-based approaches. Finally, the therapeutic potential of therapies which manipulate cardiac metabolism in the context of adjuvant cardioprotection against CTIC is examined. Together, an integrated view of the role of metabolism in pathogenesis, diagnosis and treatment is presented.

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Section: Metabolic Dysfunction Leading To Cardiotoxicity Of Specific Chemotherapiesmentioning

confidence: 99%

Cancer Therapy-Induced Cardiotoxicity—A Metabolic Perspective on Pathogenesis, Diagnosis and Therapy

Choksey

Timm

2021

IJMS

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“…We investigated whether sGES alone can describe drug action on newly obtained transcriptomics data. We analyzed expression data from cardiomyocyte-like cell lines, generated by the Drug Toxicity Signature Generation (DToxS) LINCS Center, to identify perturbagen-specific cardiomyocyte response to specific drugs (40). We observed that certain over-and underrepresented protein folds distinguish kinase inhibitor response from anthracycline drugs (Fig.…”

Section: Train Algorithm Predictmentioning

confidence: 99%

Protein structure–based gene expression signatures

Rahman

Zatorski

Hansen

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Gene expression signatures (GES) connect phenotypes to differential messenger RNA (mRNA) expression of genes, providing a powerful approach to define cellular identity, function, and the effects of perturbations. The use of GES has suffered from vague assessment criteria and limited reproducibility. Because the structure of proteins defines the functional capability of genes, we hypothesized that enrichment of structural features could be a generalizable representation of gene sets. We derive structural gene expression signatures (sGES) using features from multiple levels of protein structure (e.g., domain and fold) encoded by the mRNAs in GES. Comprehensive analyses of data from the Genotype-Tissue Expression Project (GTEx), the all RNA-seq and ChIP-seq sample and signature search (ARCHS4) database, and mRNA expression of drug effects on cardiomyocytes show that sGES are useful for characterizing biological phenomena. sGES enable phenotypic characterization across experimental platforms, facilitates interoperability of expression datasets, and describe drug action on cells.

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“… 23 In a study of primary cardiomyocyte cell lines, exposure to tyrosine kinase inhibitors correlated with a p26‐gene expression signature and effectively predicted clinical cardiotoxicity. 24 Further, protein‐protein interaction analyses helped delineate individual kinases and transcription factors that may explain the signature and the associated cardiotoxicity.…”

Section: Preclinical Evaluation Of Anticancer Drug Candidatesmentioning

confidence: 99%

Cardiovascular Safety Assessment in Cancer Drug Development

Oren

Neilan

Fradley

et al. 2021

JAHA

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The development of cardiovascular toxicity attributable to anticancer drugs is a pivotal event that is associated with cardiovascular morbidity as well as with worse cancer‐specific and overall outcomes. Although broad consensus exists regarding the importance of cardiovascular safety assessment in cancer drug development, real‐world data suggest that cardiovascular events are significantly underestimated in oncology trials. This drug safety discrepancy has profound implications on drug development decisions, risk‐benefit evaluation, formulation of surveillance and prevention protocols, and survivorship. In this article, we review the contemporary cardiovascular safety evaluation of new pharmaceuticals in hematology and oncology, spanning from in vitro pharmacodynamic testing to randomized clinical trials. We argue that cardiovascular safety assessment of anticancer drugs should be reformed and propose practical strategies, including development and validation of preclinical assays, expansion of oncology trial eligibility, incorporation of cardiovascular end points in early‐phase studies, and design of longitudinal multi‐institutional cardiotoxicity registries.

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Transcriptomic profiling of human cardiac cells predicts protein kinase inhibitor-associated cardiotoxicity

Cited by 32 publications

References 41 publications

Cancer Therapy-Induced Cardiotoxicity—A Metabolic Perspective on Pathogenesis, Diagnosis and Therapy

Cancer Therapy-Induced Cardiotoxicity—A Metabolic Perspective on Pathogenesis, Diagnosis and Therapy

Protein structure–based gene expression signatures

Cardiovascular Safety Assessment in Cancer Drug Development

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