title: Multikinase Inhibitors Induce Cutaneous Toxicity through OAT6-Mediated Uptake and MAP3K7-Driven Cell Death.
abstract: The use of multikinase inhibitors (MKI) in oncology, such as sorafenib, is associated with a cutaneous adverse event called hand-foot skin reaction (HFSR), in which sites of pressure or friction become inflamed and painful, thus significantly impacting quality of life. The pathogenesis of MKI-induced HFSR is unknown, and the only available treatment options involve dose reduction or discontinuation of therapy, which have negative effects on primary disease management. To investigate the underlying mechanisms by which sorafenib promotes keratinocyte cytotoxicity and subsequent HFSR induction, we performed a transporter-directed RNAi screen in human epidermal keratinocytes and identified SLC22A20 (OAT6) as an uptake carrier of sorafenib. Further investigations into the intracellular mechanism of sorafenib activity through in situ kinome profiling identified the mitogen-activated protein kinase MAP3K7 (TAK1) as a target of sorafenib that induces cell death. Finally, we demonstrate that sorafenib induced keratinocyte injury in vivo and that this effect could be reversed by cotreatment with the OAT6 inhibitor probenecid. Collectively, our findings reveal a novel pathway that regulates the entry of some MKIs into keratinocytes and explains the basis underlying sorafenib-induced skin toxicity, with important implications for the therapeutic management of HFSR.
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Eric I
authors.initials: EI
authors.lastname: Zimmerman
authors.affiliation: Division of Pharmaceutics, College of Pharmacy & Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Alice A
authors.initials: AA
authors.lastname: Gibson
authors.affiliation: Division of Pharmaceutics, College of Pharmacy & Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Shuiying
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Aksana
authors.initials: A
authors.lastname: Vasilyeva
authors.affiliation: Division of Pharmaceutics, College of Pharmacy & Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Shelley J
authors.initials: SJ
authors.lastname: Orwick
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Du
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Gerard P
authors.initials: GP
authors.lastname: Mascara
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Su Sien
authors.initials: SS
authors.lastname: Ong
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Taosheng
authors.initials: T
authors.lastname: Chen
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Peter
authors.initials: P
authors.lastname: Vogel
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Inaba
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Maitland
authors.affiliation: Division of Pharmaceutics, College of Pharmacy & Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Alex
authors.initials: A
authors.lastname: Sparreboom
authors.affiliation: Division of Pharmaceutics, College of Pharmacy & Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio. baker.2480@osu.edu.
authors.forename: Sharyn D
authors.initials: SD
authors.lastname: Baker
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D057125:Nuclear Receptor Subfamily 2, Group C, Member 2 / Q000378:metabolism; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000493:pharmacokinetics / Q000633:toxicity*; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000633:toxicity*; D011897:Random Allocation; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012871:Skin Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D000077157:Sorafenib; D014162:Transfection; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D020930:MAP Kinase Kinase Kinases; D009536:Niacinamide; D057125:Nuclear Receptor Subfamily 2, Group C, Member 2; D027361:Organic Anion Transporters; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D000077157:Sorafenib; D000099151:MAP Kinase Kinase Kinase 7; C492950:OAT6 protein, mouse