Publication Date

2014

Journal Title

Mol Cancer Ther

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-NH2-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. (C)2013 AACR.

Volume Number

13

Issue Number

1

Pages

221-229

Document Type

Article

Status

Faculty

Facility

School of Medicine

Primary Department

Molecular Medicine

Additional Departments

Radiation Medicine

PMID

24170769

DOI

10.1158/1535-7163.mct-13-0561


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