PLX134252

GSE91383: The antineoplastic drug, trastuzumab, dysregulates metabolism in iPSC derived cardiomyocytes.

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

Background: The targeted ERBB2 therapy, trastuzumab, has had a tremendous impact on management of patients with HER2+ breast cancer, leading to development and increased use of further HER2 targeted therapies. The major clinical side effect is cardiotoxicity but the mechanism is largely unknown. On the basis that gene expression is known to be altered in multiple models of heart failure, we examined differential gene expression of iPSC derived cardiomyocytes treated at day 11 with the ERBB2 targeted monoclonal antibody, trastuzumab for 48 hours and the small molecule tyrosine kinase inhibitor of EGFR and ERBB2.; Methods: Transcriptome sequencing was performed on four replicates from each group (48 hours untreated, 48 hours trastuzumab and 48 hours lapatinib) and differential gene expression analyses were performed on each treatment group relative to untreated cardiomyocytes.; Results: 517 and 1,358 genes were differentially expressed, p<0.05, respectively in cardiomyocytes treated with trastuzumab and lapatinib. Gene ontology analyses revealed in cardiomyocytes treated with trastuzumab, significant down-regulation of genes involved in small molecule metabolism (p=3.22x10-9) and cholesterol (p=0.01) and sterol (p=0.03) processing.; Conclusions: Our study suggests dysregulation of cardiac gene expression and metabolism as key elements of ERBB2 signaling that could potentially be early biomarkers of cardiotoxicity. SOURCE: Xuewei Wang Mayo Clinic