Multiscale mapping of transcriptomic signatures for cardiotoxic drugs

Jens Hansen (), Yuguang Xiong, Mustafa M. Siddiq, Priyanka Dhanan, Bin Hu, Bhavana Shewale, Arjun S. Yadaw, Gomathi Jayaraman, Rosa E. Tolentino, Yibang Chen, Pedro Martinez, Kristin G. Beaumont, Robert Sebra, Dusica Vidovic, Stephan C. Schürer, Joseph Goldfarb, James M. Gallo, Marc R. Birtwistle, Eric A. Sobie, Evren U. Azeloglu, Seth I. Berger, Angel Chan, Christoph Schaniel, Nicole C. Dubois () and Ravi Iyengar ()
Additional contact information
Jens Hansen: Icahn School of Medicine at Mount Sinai
Yuguang Xiong: Icahn School of Medicine at Mount Sinai
Mustafa M. Siddiq: Icahn School of Medicine at Mount Sinai
Priyanka Dhanan: Icahn School of Medicine at Mount Sinai
Bin Hu: Icahn School of Medicine at Mount Sinai
Bhavana Shewale: Icahn School of Medicine at Mount Sinai
Arjun S. Yadaw: Icahn School of Medicine at Mount Sinai
Gomathi Jayaraman: Icahn School of Medicine at Mount Sinai
Rosa E. Tolentino: Icahn School of Medicine at Mount Sinai
Yibang Chen: Icahn School of Medicine at Mount Sinai
Pedro Martinez: Icahn School of Medicine at Mount Sinai
Kristin G. Beaumont: Icahn School of Medicine at Mount Sinai
Robert Sebra: Icahn School of Medicine at Mount Sinai
Dusica Vidovic: University of Miami
Stephan C. Schürer: University of Miami
Joseph Goldfarb: Icahn School of Medicine at Mount Sinai
James M. Gallo: Icahn School of Medicine at Mount Sinai
Marc R. Birtwistle: Icahn School of Medicine at Mount Sinai
Eric A. Sobie: Icahn School of Medicine at Mount Sinai
Evren U. Azeloglu: Icahn School of Medicine at Mount Sinai
Seth I. Berger: Children’s National Research Institute
Angel Chan: Icahn School of Medicine at Mount Sinai
Christoph Schaniel: Icahn School of Medicine at Mount Sinai
Nicole C. Dubois: Icahn School of Medicine at Mount Sinai
Ravi Iyengar: Icahn School of Medicine at Mount Sinai

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Drug-induced gene expression profiles can identify potential mechanisms of toxicity. We focus on obtaining signatures for cardiotoxicity of FDA-approved tyrosine kinase inhibitors (TKIs) in human induced-pluripotent-stem-cell-derived cardiomyocytes, using bulk transcriptomic profiles. We use singular value decomposition to identify drug-selective patterns across cell lines obtained from multiple healthy human subjects. Cellular pathways affected by cardiotoxic TKIs include energy metabolism, contractile, and extracellular matrix dynamics. Projecting these pathways to published single cell expression profiles indicates that TKI responses can be evoked in both cardiomyocytes and fibroblasts. Integration of transcriptomic outlier analysis with whole genomic sequencing of our six cell lines enables us to correctly reidentify a genomic variant causally linked to anthracycline-induced cardiotoxicity and predict genomic variants potentially associated with TKI-induced cardiotoxicity. We conclude that mRNA expression profiles when integrated with publicly available genomic, pathway, and single cell transcriptomic datasets, provide multiscale signatures for cardiotoxicity that could be used for drug development and patient stratification.

Date: 2024
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DOI: 10.1038/s41467-024-52145-4

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