Abstract 17064: Enrichment of Cardiotoxic Gene Expression Profile in Human Induced Pluripotent Stem-Cell Derived Cardiomyocytes in Response to Tyrosine Kinase Inhibitor Nilotinib

Abstract

Small molecule tyrosine kinase inhibitors (TKIs) are a valuable class of therapeutics with widespread clinical utility against multiple cancers. However, there is strong evidence that TKIs are associated with cardiotoxicity and adverse cardiovascular events. Our understanding of the underlying mechanisms related to TKI induced cardiotoxicity is limited. Human iPSC derived cardiomyocytes (hiPSC-CMs) provide a flexible platform and unique model to study the underlying molecular mechanisms associated with TKI associated cardiotoxicity. In this study we describe the gene expression profile between hiPSC-CM cell lines which exhibit susceptibility vs. resistance. RNA-seq analysis was performed in hiPSC-CM cell lines from six participants in the NHLBI HyperGEN study (A to F). Experiments were performed in triplicate using sunitinib (SUN), vandetanib (VAN), gefitinib (GEF) and nilotinib (NIL). We analyzed beat rate, cell index and ATP viability as physiological measurements of CM toxicity and defined a 20% change from the normalized control as TKI susceptibility. Differential gene expression analysis was performed using DESeq2. We observed significant physiological differences between the different hiPSC-CMs after TKI treatment (beat rate, cell index and ATP viability). The most variable cell index and beat rate response was observed for NIL. Based on cell index, lines B, D, E were resistant while A, C, F were significantly more susceptible to NIL. Principal component analysis showed that the variance in gene expression was the highest after NIL treatment when compared to controls (16% for NIL; 11% for VAN; 6% for SUN and 5% for GEF). A total of 567 genes exhibited significant differential expression changes (adj. p-value ≤ 0.1) after NIL treatment in susceptible versus resistant lines. Pathway analysis showed significant enrichment for cardiotoxicity including pathways implicated in cardiac infarction, fibrosis, hypertrophy, and congestive cardiac failure. Taken together, our results identify unique gene expression changes associated with TKI cardiotoxicity. Furthermore, the variability in TKI susceptibility between different hiPSC-CM lines highlights the need to comprehensively assess cardiotoxicity in a diverse set of lines on a physiological and molecular level.