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SELECTBIO Conferences Stem Cells for Drug Discovery & Toxicity Screening 2017


Acute and Chronic Molecular Markers Causally Linked with Tyrosine Kinase Inhibitor-induced Cardiotoxicity

Huan Wang, Research Fellow, Department of Systems Biology, Harvard Medical School, Harvard Therapeutic Science Program

Tyrosine kinase inhibitors (TKIs), targeted at specific oncogenes, have significantly improved cancer patient survival, but many patients suffer from drug-induced cardiotoxicity. Toxic phenotypes range from congestive heart failure, hypertension, to cardiac arrhythmias, and onset of cardiotoxicity varies from weeks to months. This indicates that toxic effects are probably mediated by multiple biological processes and are likely determined by dose and duration of drug treatment and patients’ metabolism. We aim to illustrate underlying biological processes and molecular regulators that explain mechanisms of TKI-induced cardiotoxicity, and propose means to mitigate cardiotoxicity. To achieve this, we computationally model the relation between whole transcriptome and proteome with toxic phenotypes in human induced pluoripotent stem cells derived cardiomyocytes (iPS-CMs). Consistent with toxicity observed in clinic, Sunitinib and Sorafenib cause more significant cellular toxicity than Lapatinib and Erlotinib. Systematic profiling of gene and protein expression in iPS-CMs is highly reproducible between batches. Interestingly, gene regulation by all drugs, especially Sorafenib, is high correlated between acute (10 µM, 24h) and chronic (3.16 µM, 168h) treatment. Consistent biological functions are regulated by Sunitinib and Sorafenib, including mitochondrial respiration, metabolism, and contraction. Sorafenib induces mitochondrial uncoupling and increases glycolysis, leading to cellular toxicity. In summary, TKI-induced cardiotoxicity is mediated by numerous biological processes and molecular regulators in a dose and time dependent manner. We define a set of genes consistently regulated at RNA and protein levels as early indicators of chronic drug toxicity.

Add to Calendar ▼2017-07-10 00:00:002017-07-11 00:00:00Europe/LondonStem Cells for Drug Discovery and Toxicity Screening 2017Stem Cells for Drug Discovery and Toxicity Screening 2017 in Boston, USABoston,