High-throughput screening of tyrosine kinase inhibitor cardiotoxicity with human induced pluripotent stem cells

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Science Translational Medicine  15 Feb 2017:
Vol. 9, Issue 377, eaaf2584
DOI: 10.1126/scitranslmed.aaf2584

Failing fast for tyrosine kinase inhibitors

Discovery early in its life cycle that an anticancer drug causes heart damage (a common side effect) can halt development—saving money, time, and perhaps lives. To this end, Sharma and colleagues derived heart cells from human induced pluripotent stem cells and then examined how a battery of anticancer tyrosine kinase inhibitors altered their physiology. By measuring cell death, contraction, excitability, calcium dynamics, and signal transduction and integrating the results, they calculated a drug-specific “cardiac safety index.” This index proved highly informative, with low values corresponding to those drugs known to cause heart problems in patients. The analysis even revealed that VEGFR2-inhibiting drugs caused cells to try to compensate for the toxic effects by up-regulating protective insulin/IGF pathways, prompting the authors to devise a combination treatment that may limit the toxicity of this class of drug. This screening method is expected to reveal early on whether potential anticancer drugs are cardiotoxic.

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