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

Dabrafenib Trametinib
DOI: 10.7554/elife.00969 Publication Date: 2013-11-05T16:22:01Z
ABSTRACT
Vemurafenib and dabrafenib selectively inhibit the v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) kinase, resulting in high response rates increased survival 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, hyperproliferation. Here we show an unexpected novel effect vemurafenib/PLX4720 suppressing apoptosis through inhibition multiple off-target kinases upstream c-Jun N-terminal kinase (JNK), principally ZAK. JNK signaling suppressed contexts, including cSCC vemurafenib-treated patients, as well mice. Expression a mutant ZAK that cannot be inhibited reverses suppression activation apoptosis. Our results implicate JNK-dependent significant, independent mechanism cooperates to induce cSCC, suggesting broad implications understanding toxicities associated BRAF inhibitors their use combination therapies.
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