title: Hypothyroidism Side Effect in Patients Treated with Sunitinib or Sorafenib: Clinical and Structural Analyses.
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.
authors.affiliation: School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China.
authors.forename: Mao
authors.initials: M
authors.lastname: Shu
authors.affiliation: School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zai
authors.affiliation: School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China.
authors.forename: Beina
authors.initials: B
authors.lastname: Zhang
authors.affiliation: School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China.|School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 400044, China.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Lin
mesh_terms: D002292:Carcinoma, Renal Cell / Q000188:drug therapy; D005260:Female; D006801:Humans; D007037:Hypothyroidism / Q000139:chemically induced* / Q000453:epidemiology; D007211:Indoles / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000188:drug therapy; D008297:Male; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009536:Niacinamide / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000378:metabolism; D000077157:Sorafenib; D000077210:Sunitinib; D000097768:Retinoic Acid Receptor gamma
chemical_list: D007211:Indoles; D009536:Niacinamide; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D018168:Receptors, Retinoic Acid; D047490:Retinoid X Receptor alpha; D000077157:Sorafenib; D000077210:Sunitinib; D000097768:Retinoic Acid Receptor gamma; C082925:retinoic acid receptor beta