Abstract 17363: Inter-Individual Heterogeneity Among Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in Response to Kinase Inhibitors

Abstract

Introduction: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide unprecedented opportunities for novel investigations into the impact of individual heterogeneity on drug response. Cardio-oncology is a field of growing clinical importance due to the significant, but often sporadic, incidence of cardiotoxicity among cancer patients, including those receiving targeted therapeutics such as kinase inhibitors (KIs). Current commercially-available hiPSC-CMs are typically derived from single donors, and thus do not capture the inherent heterogeneity of patient populations. Hypothesis: We hypothesized that hiPSC-CMs derived from different individuals would display heterogeneous sensitivities to KIs. Methods: We tested iPSC-CMs from six individual participants as part of the NHLBI HyperGEN cohort. Cells were plated on 96-well ePlates (ACEA Biosciences, San Diego, CA) per manufacturer’s instructions and allowed to mature for 10-14 days prior to use. Four KIs were tested (sunitinib, vandetanib, nilotinib, and gefitinib) at concentrations ranging from Cmax to 30-fold Cmax. Toxicity was assessed using non-invasive impedance-based endpoints (beating rate, beat amplitude, and cell index) and ATP levels (Promega, Madison, WI). Results: We observed differences in baseline beating rates (BRs) among the hiPSC-CMs despite similar morphology and cardiac troponin expression levels. Following drug exposure, cell-line and drug- dependent differences in BR and cell index/viability (CI) became apparent. For example, the relatively non-cardiotoxic KI gefitinib produced few significant changes in BR or CI across all 6 cell lines, whereas KIs with black-box warnings for cardiotoxicity severely impacted these endpoints. For both vandetanib and nilotinib, statistically significant differences (p ≤ 0.05) in BR were observed between multiple cell lines at 24 hours post-exposure. Furthermore, nilotinib induced significant differences (p ≤ 0.05) in CI between multiple cell lines after 24 hours. Conclusions: Taken together, these results strongly suggest that inter-individual differences impact hiPSC-CM cardiotoxicity assessments, and support the need to test multiple cell lines during in vitro toxicity screens.