Proteomic cellular signatures of kinase inhibitor-induced cardiotoxicity

Area of Science:

• Biomedical research
• Pharmacology
• Proteomics and Transcriptomics

Background:

• The National Institutes of Health (NIH) Library of Integrated Network-Based Cellular Signatures (LINCS) program aims to understand cellular responses to drugs.
• Drug-induced cardiotoxicity from kinase inhibitors is a significant concern in clinical practice.
• Predictive models for drug toxicity are crucial for drug development and patient safety.

Purpose of the Study:

• To generate proteomic and transcriptomic signatures for predicting cardiotoxic adverse effects of FDA-approved kinase inhibitors.
• To integrate proteomic and transcriptomic data for identifying cellular signatures of cardiotoxicity.
• To enable the prediction and potential mitigation of kinase inhibitor-induced toxicity.

Main Methods:

• High-throughput shotgun proteomics experiments were performed on 308 cell line/drug combinations and 64 control lysates.
• Computational network analyses were used to integrate proteomic data with transcriptomic signatures.
• Proteomics data underwent rigorous quality control and were made publicly available on the PRIDE database.

Main Results:

• A comprehensive dataset of protein kinase inhibitor-stimulated human cardiomyocyte proteomic data was generated.
• Integration of proteomic and transcriptomic data identified potential cellular signatures of cardiotoxicity.
• The generated data and signature set are valuable for predicting drug toxicities.

Conclusions:

• The DToxS center successfully generated valuable proteomic and transcriptomic data for kinase inhibitor cardiotoxicity research.
• The integrated network-based approach provides a framework for predicting and potentially mitigating drug-induced toxicities.
• Publicly available data facilitates further research in predictive toxicology and drug safety.