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Sorafenib suppresses JNK-dependent apoptosis through inhibition of ZAK.
- Source :
-
Molecular cancer therapeutics [Mol Cancer Ther] 2014 Jan; Vol. 13 (1), pp. 221-9. Date of Electronic Publication: 2013 Oct 29. - Publication Year :
- 2014
-
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.
- Subjects :
- Antineoplastic Agents administration & dosage
Antineoplastic Agents adverse effects
Apoptosis drug effects
Carcinoma, Squamous Cell chemically induced
Carcinoma, Squamous Cell genetics
Carcinoma, Squamous Cell pathology
Cell Line, Tumor
Cell Proliferation drug effects
Cell Survival drug effects
Humans
MAP Kinase Kinase 4 metabolism
MAP Kinase Kinase Kinases
MAP Kinase Signaling System drug effects
Niacinamide administration & dosage
Niacinamide adverse effects
Phenylurea Compounds administration & dosage
Protein Kinases genetics
Skin Neoplasms chemically induced
Skin Neoplasms genetics
Skin Neoplasms pathology
Sorafenib
raf Kinases genetics
raf Kinases metabolism
Carcinoma, Squamous Cell drug therapy
Niacinamide analogs & derivatives
Phenylurea Compounds adverse effects
Protein Kinases metabolism
Skin Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1538-8514
- Volume :
- 13
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Molecular cancer therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 24170769
- Full Text :
- https://doi.org/10.1158/1535-7163.MCT-13-0561