Abstract
Anthracyclines (AC) are a class of antineoplastic drugs which are used to treat breast cancer (BC) subtypes including triple-negative BC. The 2019 Surveillance, Epidemiology, and End Results study indicates high BC survival rates and low reoccurrence with chemotherapy regimens that include AC. AC treatment, however, is associated with developing cardiovascular disease (CVD) in a subset of people, despite these patients having no history of CVD. Because CVD is typically irreversible, understanding patient susceptibility to AC toxicity is critical to cancer treatment management and long-term patient survival. As a first step towards understanding the genetic and mechanistic basis for AC-induced cardiotoxicity, we have developed an in vitro cardiomyocyte (CM) model using a panel of four genotyped induced-Pluripotent Stem Cell (iPSC) lines to test the effects of three AC (Doxorubicin, Epirubicin and Daunorubicin) and two non-AC (Mitoxantrone and Trastuzumab) BC drugs. We can reliably differentiate beating CMs at a median purity 90.5% based on the expression of cardiac-specific troponin T. Drug exposure for 48 hours reveals cardiotoxicity at micromolar concentrations across all drugs except for Trastuzumab, with Daunorubicin and Mitoxantrone exhibiting the greatest effect. We observe mRNA expression changes of stress response genes such as p53 within six hours of drug treatment, suggesting that an early transcriptional response mediates these effects. Using this model, we plan to measure the global transcriptional response to drug exposure across individuals and correlate these changes with each individual’s genetic variants to gain insight into cardiotoxicity susceptibility.
Published Version
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