Proteomic cellular signatures of kinase inhibitor-induced cardiotoxicity

Yuguang Xiong,Tong Chen,Hong Li,Joseph Goldfarb,Evren U Azeloglu,Jens Hansen,Yibang Chen,Ravi Iyengar,Gomathi Jayaraman,Dusica Vidovic,Tong Liu,Stephan Schürer,Bin Hu,Eric A Sobie,Marc R Birtwistle

doi:10.1038/s41597-021-01114-3

Abstract

Drug Toxicity Signature Generation Center (DToxS) at the Icahn School of Medicine at Mount Sinai is one of the centers for the NIH Library of Integrated Network-Based Cellular Signatures (LINCS) program. Its key aim is to generate proteomic and transcriptomic signatures that can predict cardiotoxic adverse effects of kinase inhibitors approved by the Food and Drug Administration. Towards this goal, high throughput shotgun proteomics experiments (308 cell line/drug combinations +64 control lysates) have been conducted. Using computational network analyses, these proteomic data can be integrated with transcriptomic signatures, generated in tandem, to identify cellular signatures of cardiotoxicity that may predict kinase inhibitor-induced toxicity and enable possible mitigation. Both raw and processed proteomics data have passed several quality control steps and been made publicly available on the PRIDE database. This broad protein kinase inhibitor-stimulated human cardiomyocyte proteomic data and signature set is valuable for prediction of drug toxicities.

Highlights

Background & SummaryProtein kinase inhibitors (KIs) belong to a class of targeted therapeutics that are being increasingly used in treatment of various cancers[1]
Since different omics assays show varied sensitivities[5] and offer complementary molecular information on the cellular phenotypic state[6], in order to develop a comprehensive understanding of the cellular responses to KIs, we use network analyses[7] to combine differential expression of genes and gene products in human cardiomyocytes treated by FDA approved KIs, analyzed using both transcriptomic and proteomic methods
We present the proteomic portion of the effects of KIs on human cardiomyocytes

Summary

Introduction

Background & SummaryProtein kinase inhibitors (KIs) belong to a class of targeted therapeutics that are being increasingly used in treatment of various cancers[1]. To quality control the LC-MS/MS system performance, we ran a Pierce HeLa Protein Digest Standard (Pierce, Cat# 88329) on the instrument, prior to running each set of drug-treated samples.

Results

Conclusion