Adaptation of Human iPSC-Derived Cardiomyocytes to Tyrosine Kinase Inhibitors Reduces Acute Cardiotoxicity via Metabolic Reprogramming

May 22, 2019

Master drug stocks were stored at 10 mM in DMSO for TKIs and 2 M in water for 2DG with 0.03% Tween 20. Tween was added to facilitate dispensing of drugs in aqueous solvent by the HP D300 dispenser

Tyrosine kinase inhibitors (TKIs) are widely used to treat solid tumors but can be cardiotoxic. The molecular basis for this toxicity and its relationship to therapeutic mechanisms remain unclear; we therefore undertook a systems-level analysis of human cardiomyocytes (CMs) exposed to four TKIs. CMs differentiated from human induced pluripotent stem cells (hiPSCs) were exposed to sunitinib, sorafenib, lapatinib, or erlotinib, and responses were assessed by functional assays, microscopy, RNA sequencing, and mass spectrometry (GEO: GSE114686; PRIDE: PXD012043). TKIs have diverse effects on hiPSC-CMs distinct from inhibition of tyrosine-kinase-mediated signal transduction; cardiac metabolism is particularly sensitive. Following sorafenib treatment, oxidative phosphorylation is downregulated, resulting in a profound defect in mitochondrial energetics. Cells adapt by upregulating aerobic glycolysis. Adaptation makes cells less acutely sensitive to sorafenib but may have long-term negative consequences. Thus, CMs exhibit adaptive responses to anti-cancer drugs conceptually similar to those previously shown in tumors to mediate drug resistance. Copyright Š 2019 The Authors. Published by Elsevier Inc. All rights reserved.

Wang, H; Sheehan, RP; Palmer, AC; Everley, RA; Boswell, SA; Ron-Harel, N; Ringel, AE; Holton, KM; Jacobson, CA; Erickson, AR; Maliszewski, L; Haigis, MC; Sorger, PK;

Journal: Cell Syst Pages: 412-426.e7

Original article (31078528)