{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T22:26:14Z","timestamp":1787955974959,"version":"build-2784847793"},"reference-count":50,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2019,9,3]],"date-time":"2019-09-03T00:00:00Z","timestamp":1567468800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100004052","name":"King Abdullah University of Science and Technology","doi-asserted-by":"publisher","award":["FCC\/1\/1976-25"],"award-info":[{"award-number":["FCC\/1\/1976-25"]}],"id":[{"id":"10.13039\/501100004052","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["HA 7346\/2-1"],"award-info":[{"award-number":["HA 7346\/2-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010127","name":"J\u00fcrgen Manchot Stiftung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010127","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Allergy"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>In recent years, the BRAF inhibitor vemurafenib has been successfully established in the therapy of advanced melanoma. Despite its superior efficacy, the use of vemurafenib is limited by frequent inflammatory cutaneous adverse events that affect patients\u2019 quality of life and may lead to dose reduction or even cessation of anti\u2010tumor therapy. To date, the molecular and cellular mechanisms of vemurafenib\u2010induced rashes have remained largely elusive.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this study, we deployed immunohistochemistry, RT\u2010qPCR, flow cytometry, lymphocyte activation tests, and different cell\u2010free protein\u2010interaction assays.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We here demonstrate that vemurafenib inhibits the downstream signaling of the canonical pathway of aryl hydrocarbon receptor (AhR) in vitro, thereby inducing the expression of proinflammatory cytokines (eg, <jats:italic>TNF<\/jats:italic>) and chemokines (eg, <jats:italic>CCL5<\/jats:italic>). In line with these results, we observed an impaired expression of AhR\u2010regulated genes (eg, <jats:italic>CYP1A1<\/jats:italic>) and an upregulation of the corresponding proinflammatory genes in vivo. Moreover, results of lymphocyte activation tests showed the absence of drug\u2010specific T cells in respective patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Taken together, we obtained no hint of an underlying sensitization against vemurafenib but found evidence suggesting that vemurafenib enhances proinflammatory responses by inhibition of canonical AhR signaling. Our findings contribute to our understanding of the central role of the AhR in skin inflammation and may point toward a potential role for topical AhR agonists in supportive cancer care.<\/jats:p><\/jats:sec>","DOI":"10.1111\/all.13972","type":"journal-article","created":{"date-parts":[[2019,7,3]],"date-time":"2019-07-03T19:08:57Z","timestamp":1562180937000},"page":"2437-2448","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Vemurafenib acts as an aryl hydrocarbon receptor antagonist: Implications for inflammatory cutaneous adverse events"],"prefix":"10.1111","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3990-8230","authenticated-orcid":false,"given":"Heike C.","family":"Hawerkamp","sequence":"first","affiliation":[{"name":"Department of Dermatology, Medical Faculty Heinrich\u2010Heine\u2010University Duesseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Kislat","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Medical Faculty Heinrich\u2010Heine\u2010University Duesseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter A.","family":"Gerber","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Medical Faculty Heinrich\u2010Heine\u2010University Duesseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marius","family":"Pollet","sequence":"additional","affiliation":[{"name":"Leibniz\u2010Research Institute for Environmental Medicine Duesseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina M.","family":"Rolfes","sequence":"additional","affiliation":[{"name":"Leibniz\u2010Research Institute for Environmental Medicine Duesseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anatoly A.","family":"Soshilov","sequence":"additional","affiliation":[{"name":"Department of Environmental Toxicology University of California Davis CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael S.","family":"Denison","sequence":"additional","affiliation":[{"name":"Department of Environmental Toxicology University of California Davis CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Afaque A.","family":"Momin","sequence":"additional","affiliation":[{"name":"King Abdullah University of Science and Technology (KAUST) Computational Bioscience Research Center (CBRC), Division of Biological and Environmental Sciences and Engineering (BESE) Thuwal Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan T.","family":"Arold","sequence":"additional","affiliation":[{"name":"King Abdullah University of Science and Technology (KAUST) Computational Bioscience Research Center (CBRC), Division of Biological and Environmental Sciences and Engineering (BESE) Thuwal Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angeliki","family":"Datsi","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Medical Faculty Heinrich\u2010Heine\u2010University Duesseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan A.","family":"Braun","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Medical Faculty Heinrich\u2010Heine\u2010University Duesseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P\u00e9ter","family":"Ol\u00e1h","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Medical Faculty Heinrich\u2010Heine\u2010University Duesseldorf Germany"},{"name":"Department of Dermatology, Venereology and Oncodermatology University of P\u00e9cs P\u00e9cs Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario E.","family":"Lacouture","sequence":"additional","affiliation":[{"name":"Dermatology Service, Department of Medicine Memorial Sloan\u2010Kettering Cancer Center New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean","family":"Krutmann","sequence":"additional","affiliation":[{"name":"Leibniz\u2010Research Institute for Environmental Medicine Duesseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Haarmann\u2010Stemmann","sequence":"additional","affiliation":[{"name":"Leibniz\u2010Research Institute for Environmental Medicine Duesseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard","family":"Homey","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Medical Faculty Heinrich\u2010Heine\u2010University Duesseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Meller","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Medical Faculty Heinrich\u2010Heine\u2010University Duesseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,9,3]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1103782"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1468-3083.2012.04546.x"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc1114329"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/CMR.0b013e3283573437"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.114.009001"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.112.195339"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfq217"},{"key":"e_1_2_9_9_1","first-page":"8","article-title":"Analysis of the aryl hydrocarbon receptor (AhR) signal transduction pathway","volume":"4","author":"Denison MS","year":"2002","journal-title":"Curr Protoc Toxicol."},{"issue":"7","key":"e_1_2_9_10_1","doi-asserted-by":"crossref","first-page":"1654","DOI":"10.1016\/j.ejca.2013.01.015","article-title":"The European Medicines Agency review of vemurafenib (Zelboraf(R)) for the treatment of adult patients with BRAF V600 mutation\u2010positive unresectable or metastatic melanoma: summary of the scientific assessment of the Committee for Medicinal Products for Human Use","volume":"49","author":"Rocha DS","year":"2013","journal-title":"Eur J Cancer."},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI76539"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)60398-5"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.164.7.3465"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1398-9995.2007.01516.x"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1515\/bc.2010.128"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-014-1321-8"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M002466200"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1054\/bjoc.2000.1546"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2016.06.024"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm049323m"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2005.08.162"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)53580-8"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-2923"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.16465"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfr218"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3005886"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1112302"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0058721"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature08833"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1408868"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamadermatol.2014.838"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00281-015-0540-2"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12757"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1398-9995.2007.01607.x"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1111\/all.12618"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1177\/1758834014566428"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1021\/tx200141p"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.53.3.438"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0044547"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2008.10.013"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2008.09.013"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2015.285"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2014.04.019"},{"issue":"2","key":"e_1_2_9_44_1","first-page":"917","article-title":"Coal tar induces AHR\u2010dependent skin barrier repair in atopic dermatitis","volume":"123","author":"van den Bogaard EH","year":"2013","journal-title":"J Clin Invest."},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00337-09"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-06951-2"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)60868-X"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2014.09.002"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1111\/jdv.13892"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2017.05.004"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfr249"}],"container-title":["Allergy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/all.13972","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/all.13972","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/all.13972","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,30]],"date-time":"2023-08-30T16:00:51Z","timestamp":1693411251000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/all.13972"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,3]]},"references-count":50,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2019,12]]}},"alternative-id":["10.1111\/all.13972"],"URL":"https:\/\/doi.org\/10.1111\/all.13972","archive":["Portico"],"relation":{},"ISSN":["0105-4538","1398-9995"],"issn-type":[{"value":"0105-4538","type":"print"},{"value":"1398-9995","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,3]]},"assertion":[{"value":"2018-07-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-05-21","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-09-03","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}