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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / adverse effects
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Apoptosis / drug effects
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Carcinoma, Squamous Cell / chemically induced
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Carcinoma, Squamous Cell / drug therapy*
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Carcinoma, Squamous Cell / genetics
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Carcinoma, Squamous Cell / pathology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Humans
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MAP Kinase Kinase 4 / metabolism
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MAP Kinase Kinase Kinases
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MAP Kinase Signaling System / drug effects
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Niacinamide / administration & dosage
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Niacinamide / adverse effects
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Niacinamide / analogs & derivatives*
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Phenylurea Compounds / administration & dosage
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Phenylurea Compounds / adverse effects*
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Protein Kinases / genetics
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Protein Kinases / metabolism*
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Skin Neoplasms / chemically induced
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Skin Neoplasms / drug therapy*
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Skin Neoplasms / genetics
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Skin Neoplasms / pathology
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Sorafenib
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raf Kinases / genetics
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raf Kinases / metabolism
Substances
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Antineoplastic Agents
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Phenylurea Compounds
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Niacinamide
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Sorafenib
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Protein Kinases
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raf Kinases
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MAP Kinase Kinase Kinases
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MAP3K20 protein, human
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MAP Kinase Kinase 4