Abstract
Tyrosine kinase inhibitors (TKIs) provide more effective targeted treatments for cancer, but are subject to a variety of adverse effects, such as hypothyroidism. TKI-induced hypothyroidism is a highly complicated issue, because of not only the unrealized toxicological mechanisms, but also different incidences of individual TKI drugs. While sunitinib is suspected for causing thyroid dysfunction more often than other TKIs, sorafenib is believed to be less risky. Here we integrated clinical data and in silico drug-protein interactions to examine the pharmacological distinction between sunitinib and sorafenib. Statistical analysis on the FDA Adverse Event Reporting System (FAERS) confirmed that sunitinib is more concurrent with hypothyroidism than sorafenib, which was observed in both female and male patients. Then, we used docking method and identified 3 proteins specifically binding to sunitinib but not sorafenib, i.e., retinoid X receptor alpha, retinoic acid receptors beta and gamma. As potential off-targets of sunitinib, these proteins are well known to assemble with thyroid hormone receptors, which can explain the profound impact of sunitinib on thyroid function. Taken together, we established a strategy of integrated analysis on clinical records and drug off-targets, which can be applied to explore the molecular basis of various adverse drug reactions.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Carcinoma, Renal Cell / drug therapy
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Female
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Humans
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Hypothyroidism / chemically induced*
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Hypothyroidism / epidemiology
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Indoles / adverse effects
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Indoles / chemistry*
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Indoles / pharmacology*
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Kidney Neoplasms / drug therapy
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Male
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Models, Molecular
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Molecular Docking Simulation
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Niacinamide / adverse effects
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Niacinamide / analogs & derivatives*
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Niacinamide / chemistry
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Niacinamide / pharmacology
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Phenylurea Compounds / adverse effects
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Phenylurea Compounds / chemistry*
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Phenylurea Compounds / pharmacology*
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Protein Kinase Inhibitors / adverse effects
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology
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Pyrroles / adverse effects
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Pyrroles / chemistry*
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Pyrroles / pharmacology*
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Receptors, Retinoic Acid / metabolism
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Retinoic Acid Receptor gamma
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Retinoid X Receptor alpha / metabolism
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Sorafenib
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Sunitinib
Substances
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Indoles
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Phenylurea Compounds
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Protein Kinase Inhibitors
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Pyrroles
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Receptors, Retinoic Acid
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Retinoid X Receptor alpha
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retinoic acid receptor beta
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Niacinamide
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Sorafenib
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Sunitinib
Grants and funding
This study was supported by the National Natural Science Foundation of China (
http://www.nsfc.gov.cn/, 31170747, 81171508), Key Project of Natural Science Foundation of Chong Qing (CSTC 2013JJB10004). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.