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Elife. 2013 Nov 5;2:e00969. doi: 10.7554/eLife.00969.

BRAF inhibitors suppress apoptosis through off-target inhibition of JNK signaling.

Author information

1
Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, United States.

Abstract

Vemurafenib and dabrafenib selectively inhibit the v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) kinase, resulting in high response rates and increased survival in melanoma. Approximately 22% of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma (cSCC) during therapy. The prevailing explanation for this is drug-induced paradoxical ERK activation, resulting in hyperproliferation. Here we show an unexpected and novel effect of vemurafenib/PLX4720 in suppressing apoptosis through the inhibition of multiple off-target kinases upstream of c-Jun N-terminal kinase (JNK), principally ZAK. JNK signaling is suppressed in multiple contexts, including in cSCC of vemurafenib-treated patients, as well as in mice. Expression of a mutant ZAK that cannot be inhibited reverses the suppression of JNK activation and apoptosis. Our results implicate suppression of JNK-dependent apoptosis as a significant, independent mechanism that cooperates with paradoxical ERK activation to induce cSCC, suggesting broad implications for understanding toxicities associated with BRAF inhibitors and for their use in combination therapies. DOI: http://dx.doi.org/10.7554/eLife.00969.001.

KEYWORDS:

apoptosis; cancer; melanoma; protein kinase; squamous cell carcinoma; targeted therapy

PMID:
24192036
PMCID:
PMC3814616
DOI:
10.7554/eLife.00969
[Indexed for MEDLINE]
Free PMC Article
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