title: Sorafenib suppresses JNK-dependent apoptosis through inhibition of ZAK.
abstract: Sorafenib is U.S. Food and Drug Adminstration-approved for the treatment of renal cell carcinoma and hepatocellular carcinoma and has been combined with numerous other targeted therapies and chemotherapies in the treatment of many cancers. Unfortunately, as with other RAF inhibitors, patients treated with sorafenib have a 5% to 10% rate of developing cutaneous squamous cell carcinoma (cSCC)/keratoacanthomas. Paradoxical activation of extracellular signal-regulated kinase (ERK) in BRAF wild-type cells has been implicated in RAF inhibitor-induced cSCC. Here, we report that sorafenib suppresses UV-induced apoptosis specifically by inhibiting c-jun-NH(2)-kinase (JNK) activation through the off-target inhibition of leucine zipper and sterile alpha motif-containing kinase (ZAK). Our results implicate suppression of JNK signaling, independent of the ERK pathway, as an additional mechanism of adverse effects of sorafenib. This has broad implications for combination therapies using sorafenib with other modalities that induce apoptosis.
authors.affiliation: Corresponding Author: Kenneth Y. Tsai, Departments of Dermatology and Immunology, University of Texas MD Anderson Cancer Center, 7455 Fannin, Unit 907, Houston, TX 77054. kytsai@mdanderson.org.
authors.forename: Harina
authors.initials: H
authors.lastname: Vin
authors.forename: Grace
authors.initials: G
authors.lastname: Ching
authors.forename: Sandra S
authors.initials: SS
authors.lastname: Ojeda
authors.forename: Charles H
authors.initials: CH
authors.lastname: Adelmann
authors.forename: Vida
authors.initials: V
authors.lastname: Chitsazzadeh
authors.forename: David W
authors.initials: DW
authors.lastname: Dwyer
authors.forename: Haiching
authors.initials: H
authors.lastname: Ma
authors.forename: Karin
authors.initials: K
authors.lastname: Ehrenreiter
authors.forename: Manuela
authors.initials: M
authors.lastname: Baccarini
authors.forename: Rosamaria
authors.initials: R
authors.lastname: Ruggieri
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Curry
authors.forename: Ana M
authors.initials: AM
authors.lastname: Ciurea
authors.forename: Madeleine
authors.initials: M
authors.lastname: Duvic
authors.forename: Naifa L
authors.initials: NL
authors.lastname: Busaidy
authors.forename: Nizar M
authors.initials: NM
authors.lastname: Tannir
authors.forename: Kenneth Y
authors.initials: KY
authors.lastname: Tsai
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000077157:Sorafenib; D048490:raf Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; D011494:Protein Kinases; D048490:raf Kinases; D020930:MAP Kinase Kinase Kinases; C413047:MAP3K20 protein, human; D048670:MAP Kinase Kinase 4