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Multikinase Inhibitors Induce Cutaneous Toxicity Through OAT6-Mediated Uptake and MAP3K7-Driven Cell Death Eric I

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Multikinase Inhibitors Induce Cutaneous Toxicity Through OAT6-Mediated Uptake and MAP3K7-Driven Cell Death Eric I Published OnlineFirst December 17, 2015; DOI: 10.1158/0008-5472.CAN-15-0694 Cancer Therapeutics, Targets, and Chemical Biology Research Multikinase Inhibitors Induce Cutaneous Toxicity through OAT6-Mediated Uptake and MAP3K7-Driven Cell Death Eric I. Zimmerman1, Alice A. Gibson2, Shuiying Hu2, Aksana Vasilyeva1, Shelley J. Orwick2, Guoqing Du1, Gerard P. Mascara1, Su Sien Ong3, Taosheng Chen3, Peter Vogel4, Hiroto Inaba5, Michael L. Maitland6, Alex Sparreboom2, and Sharyn D. Baker2 Abstract The use of multikinase inhibitors (MKI) in oncology, such as (OAT6) as an uptake carrier of sorafenib. Further investigations sorafenib, is associated with a cutaneous adverse event called into the intracellular mechanism of sorafenib activity through hand–foot skin reaction (HFSR), in which sites of pressure or in situ kinome profiling identified the mitogen-activated pro- friction become inflamed and painful, thus significantly tein kinase MAP3K7 (TAK1) as a target of sorafenib that induces impacting quality of life. The pathogenesis of MKI-induced cell death. Finally, we demonstrate that sorafenib induced HFSR is unknown, and the only available treatment options keratinocyte injury in vivo and that this effect could be reversed involve dose reduction or discontinuation of therapy, which by cotreatment with the OAT6 inhibitor probenecid. Collec- have negative effects on primary disease management. To tively, our findings reveal a novel pathway that regulates the investigate the underlying mechanisms by which sorafenib entry of some MKIs into keratinocytes and explains the basis promotes keratinocyte cytotoxicity and subsequent HFSR underlying sorafenib-induced skin toxicity, with important induction, we performed a transporter-directed RNAi screen implications for the therapeutic management of HFSR. Cancer in human epidermal keratinocytes and identified SLC22A20 Res; 76(1); 117–26. Ó2015 AACR. Introduction myriad of mechanisms, leading ultimately to lack of efficacy. Moreover, although kinase inhibitors offer possibly a number of In oncology, the last two decades have seen a dramatic tran- important theoretical advantages over conventional cytotoxic sition from the use of traditional cytotoxic chemotherapy to the chemotherapy, they are still afflicted by some of the same pro- emergence of a new paradigm in rational drug design coupled blems, including an extensive interindividual pharmacokinetic with an uprising in the development of targeted agents, including variability, the existence of a rather narrow therapeutic window, the kinase inhibitors. To date, more than 20 different kinase and the occurrence of multiple, debilitating adverse events (1). inhibitors have received approval by the FDA for the treatment Cutaneous adverse effects are among the most frequently of a variety of diseases that were previously essentially resistant to observed toxicities with many kinase inhibitors, and their inten- standard chemotherapy, and many more can be expected to sity can significantly affect both quality of life and health care become available in the future (1). However, despite the success economics (2). A particularly painful complication seen most of these agents in specific disease settings, many kinase inhibitors frequently during the early weeks of use with multikinase inhi- face significant challenges due to their susceptibility to de novo bitors (MKI), such as sorafenib, sunitinib, and pazopanib, is resistance and/or the occurrence of acquired resistance through a called hand–foot skin reaction (HFSR), in which hyperkeratotic 1 plaques develop predominantly over sites of pressure or friction Department of Pharmaceutical Sciences, St. Jude Children's Research fi fl Hospital, Memphis, Tennessee. 2Division of Pharmaceutics, College of (3, 4). These plaques may have signi cant in ammation and Pharmacy & Comprehensive Cancer Center,The Ohio State University, xerotic hyperkeratosis, often in a bilateral symmetric distribution, Columbus, Ohio. 3Department of Chemical Biology and Therapeutics, causing pain and debilitation that interfere with activities of daily St. Jude Children's Research Hospital, Memphis, Tennessee. 4Depart- ment of Pathology, St. Jude Children's Research Hospital, Memphis, living (2). Sequential biopsy specimens have revealed progressive Tennessee. 5Department of Oncology, St. Jude Children's Research accumulation of hyperkeratosis with focal parakeratosis. The Hospital, Memphis, Tennessee. 6Section of Hematology/Oncology, clinical incidence of HFSR varies among MKIs with a particularly Department of Medicine, The University of Chicago, Chicago, Illinois. high incidence being observed with sorafenib (Supplementary Note: Supplementary data for this article are available at Cancer Research Table S1; ref. 4), and does not appear to be related to increased Online (http://cancerres.aacrjournals.org/). excretion of MKIs through sweat (5). The pathogenesis of MKI- Corresponding Author: Sharyn D. Baker, Division of Pharmaceutics, College of induced HFSR remains currently unknown, and the only demon- Pharmacy & Comprehensive Cancer Center, The Ohio State University, 500 W. strably effective treatment options involve dose reduction or 12th St., Columbus, OH 43210. Phone: 614-685-6014, Fax: 614-688-4028; E-mail: discontinuation of therapy, which have negative effects on disease [email protected] management (6, 7). Here, we provide evidence that sorafenib can doi: 10.1158/0008-5472.CAN-15-0694 extensively accumulate into human epidermal keratinocytes Ó2015 American Association for Cancer Research. mediated by the organic anion transporter SLC22A20 (OAT6) www.aacrjournals.org 117 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst December 17, 2015; DOI: 10.1158/0008-5472.CAN-15-0694 Zimmerman et al. A Sorafenib Lot 932013 Imatinib Lot 932013 B C 6,000 Sorafenib Lot 1443683 Imatinib Lot 1443683 Sorafenib (μmol/L) Imatinib (μmol/L) Lot 932013 125 0 0.5 1.0 2.55.0 10.0 0.5 1.02.5 5.0 10.0 Lot 1443683 PARP 4,000 100 Cleaved PARP 75 Pro- 2,000 50 caspase 3 (% control) Cell viability Drug uptake (pmol/mg) 25 Cleaved 0 caspase 3 ib 0 nib 0.01 0.1 1 10 Sunitin Imatinib Nilotinib Sorafe Pazopanib Dasatinib Sorafenib uptake (% control) D EFInhibited SLC 150 0 50 100 families Vehicle None 100 125 Niflumic acid SLC6A Furosemide * SLC12A, SLC22A ** Probenecid 75 100 * SLC22A 5-OH-L-Tryptophan SLC22A, SLC36A L-Arginine * SLC38A *** 50 75 Hemicholinium-3 * SLC22A, SLC44A (% control) Vehicle None Sorafenib uptakeSorafenib 50 25 Sorafenib uptake Sorafenib Hemicholinium-3 *** SLC22A, SLC44A (% control siRNA) Homovanillic acid SLC22A 25 *** 0 Transporters Probenecid *** SLC22A Lot: 932013 1443683 Figure 1. OAT6 mediates sorafenib uptake in HEKa. A, HEKa from two individual lots were treated with sorafenib or imatinib for 72 hours and cell viability was measured in a MTT assay (2–3 experiments, n ¼ 12–18). B, cleaved PARP and caspase-3 were assessed by Western blot analysis after 24 hours. C, intracellular accumulation of kinase inhibitors (1 mmol/L, 5 min) in HEKa (two experiments, n ¼ 6). D, intracellular accumulation of sorafenib (1 mmol/L, 15 min) in HEKa 48 hours after siRNA (25 nmol/L) transfection (n ¼ 7). Red line indicates 75% uptake and red data points indicate 75% uptake compared with control conditions. E, effect of transporter inhibitors (0.2–1.0 mmol/L; blue bars) and OAT inhibitors (100 mmol/L; red bars) on intracellular accumulation of sorafenib (1 mmol/L, 15 minutes) in HEKa (blue bars; n ¼ 2–6). F, intracellular accumulation of sorafenib (1 mmol/L, 15 minutes) in HEKa 48 hours after transfection with OAT6-targeted siRNA (25 nmol/L; 2–3 experiments, n ¼ 6–9; control siRNA, filled bars; OAT6 siRNA, unfilled bars). Mean gene expression (relative to control siRNA 48-hour posttransfection) was 45 Æ 1% and 39 Æ 3%. Data represent the mean Æ SEM (Ã, P < 0.05; ÃÃ, P < 0.01; ÃÃÃ, P < 0.001). and we identified the mitogen-activated protein kinase MAP3K7 primer and probe pairs for SLC22A6, SLC22A7, SLC22A8, (TAK1) as a novel target of sorafenib causing keratinocyte cell SLC22A9, SLC22A10, SLC22A11, SLC22A20, and GAPDH were death. Finally, we demonstrate that sorafenib induces injury to purchased from Life Technologies. GeneChip human genome keratinocytes in vivo, and that this effect can be reversed by U133 Plus 2.0 microarrays were purchased from Affymetrix. cotreatment with the OAT6 inhibitor probenecid. Cell culture and viability assays Materials and Methods Human primary keratinocytes [HEKa; Life Technologies, Lot 932013 and Lot 1443683] were cultured on collagen-coated flasks Chemicals and reagents in EpiLife medium (Life Technologies) according to the product Hemicholinum-3, homovanillic acid, and probenecid were instructions. Mouse primary epithelial keratinocytes were pur- 3 purchased from Sigma-Aldrich. [ H]Ddasatinib [specific chased from CellNTec and propagated using CNT-PR medium activity (SA) ¼ 10.2 Ci/mmol; radiochemical purity 99.7%], according to the product instructions. Cells were maintained at 3 ¼ [ H]imatinib (SA 1.7 Ci/mmol; radiochemical purity 37 C in humidified air containing 5% CO2. Cell viability was 3 99.9%), [ H]nilotinib (SA ¼ 3.9 Ci/mmol; radiochemical purity measured using either MTT reagent (Life Technologies) or Cell- 3 99.7%), [ H]pazopanib (SA ¼ 1.0 Ci/mmol; radiochemical purity Titer-Glo (Promega) according to the manufacturer's instructions 3 99.1%), [ H]sorafenib (SA ¼ 2.2 Ci/mmol; radiochemical purity on a Biotek mQuant microplate spectrophotometer.
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