RT Journal Article
SR Electronic
T1 Adaptation of human iPSC-derived cardiomyocytes to tyrosine kinase inhibitors reduces acute cardiotoxicity via metabolic reprogramming
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 365841
DO 10.1101/365841
A1 Huan Wang
A1 Robert P. Sheehan
A1 Adam C. Palmer
A1 Robert A. Everley
A1 Sarah A. Boswell
A1 Noga Ron-Harel
A1 Alison E. Ringel
A1 Kristina M. Holton
A1 Connor A. Jacobson
A1 Alison R. Erickson
A1 Laura Maliszewski
A1 Marcia C. Haigis
A1 Peter K. Sorger
YR 2019
UL http://biorxiv.org/content/early/2019/03/12/365841.abstract
AB 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 exposed to four TKIs. Cardiomyocytes (CMs) differentiated from human induced pluripotent stem cells (hiPSCs) were exposed to sunitinib, sorafenib, lapatinib or erlotinib and responses 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 down-regulated, 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, cardiomyocytes exhibit adaptive responses to anti-cancer drugs conceptually similar to those previously shown in tumors to mediate drug resistance.