Year: 2019
Type: review
Abstract: Nephrotoxicity is a critical adverse event that leads to discontinuation of kinase inhibitor (KI) treatment. Here we show, through meta-analyses of FDA Adverse Event Reporting System, that dasatinib is associated with high risk for glomerular toxicity that is uncoupled from hypertension, suggesting a direct link between dasatinib and podocytes. We further investigate the cellular effects of dasatinib and other comparable KIs with varying risks of nephrotoxicity. Dasatinib treated podocytes show significant changes in focal adhesions, actin cytoskeleton, and morphology that are not observed with other KIs. We use phosphoproteomics and kinome profiling to identify the molecular mechanisms of dasatinib-induced injury to the actin cytoskeleton, and atomic force microscopy to quantify impairment to cellular biomechanics. Furthermore, chronic administration of dasatinib in mice causes reversible glomerular dysfunction, loss of stress fibers, and foot process effacement. We conclude that dasatinib induces nephrotoxicity through altered podocyte actin cytoskeleton, leading to injurious cellular biomechanics.
Source: Nature Communications
Authors: Rhodora C. Calizo, Smiti Bhattacharya, J. G. Coen van Hasselt, Chengguo Wei, Jenny S. Wong, Robert J. Wiener, Xuhua Ge, Nicholas J. Wong, Jia-Jye Lee, Christina M. Cuttitta, Gomathi Jayaraman, Vivienne H. Au, William Janssen, Tong Liu, Hong Li, Fadi Salem, Edgar A. Jaimes, Barbara Murphy, Kirk N. Campbell, Evren U. Azeloglu
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,200
Funders: American Society of Nephrology, Foundation for Anesthesia Education and Research, Nephcure Foundation, ASN Foundation for Kidney Research, European Commission, National Institutes of Health, National Human Genome Research Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: Drug Combination Signatures for Prediction and Mitigation of Toxicity, Predicting Cardiotoxicity Induced by Kinase Inhibitors: From Systems Biology to Systems Pharmacology, The role of dendrin in glomerular disease progression, Systems mechanisms underlying cell shape based phenotypic switches, Spatial Models of Cell Regulatory Networks, G8518393024, Cancer Center Support Grant, Mechanosensitive determinants of podocyte physiology
OpenAlex ID: W2943024004