Sorafenib Suppresses JNK-Dependent Apoptosis through Inhibition of ZAK

Autor(en)

Harina Vin, Grace Ching, Sandra S. Ojeda, Charles H. Adelmann, Vida Chitsazzadeh, David W. Dwyer, Haiching Ma, Karin Ehrenreiter, Manuela Baccarini, Rosamaria Ruggieri, Jonathan L. Curry, Ana M. Ciurea, Madeleine Duvic, Naifa L. Busaidy, Nizar M. Tannir, Kenneth Y. Tsai

Abstrakt

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.

Organisation(en)

Department für Mikrobiologie, Immunbiologie und Genetik

Externe Organisation(en)

University of Texas MD Anderson Cancer Center, University of Texas Health Science Center at Houston, Northwell Health, Reaction Biology Corporation

Journal

Molecular Cancer Therapeutics

Band

13

Seiten

221-229

Anzahl der Seiten

9

ISSN

1535-7163

DOI

https://doi.org/10.1158/1535-7163.MCT-13-0561

Publikationsdatum

01-2014

Peer-reviewed

Ja

ÖFOS 2012

106052 Zellbiologie

Schlagwörter

ASJC Scopus Sachgebiete

Oncology, Cancer Research

Sustainable Development Goals

SDG 3 – Gesundheit und Wohlergehen

Link zum Portal

https://ucrisportal.univie.ac.at/de/publications/sorafenib-suppresses-jnkdependent-apoptosis-through-inhibition-of-zak(212376ad-c208-4bb4-88cc-82cb73bf9830).html