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

• DOI: 10.7554/elife.00969
• Publication Date: 2013-11-05T16:22:01Z
• Authors: Harina Vin; Sandra S Ojeda; Grace Ching; Marco L Leung; Vida Chitsazzadeh; David W Dwyer; Charles H Adelmann; Monica Restrepo; Kristen N Richards; Larissa R Stewart; Lili Du; Scarlett B Ferguson; Deepavali Chakrav...; Karin Ehrenreiter; Manuela Baccarini; Rosamaria Ruggieri; Jonathan L Curry; Kevin B Kim; Ana M Ciurea; Madeleine Duvic; Victor G Prieto; Stephen E Ullrich; Kevin N Dalby; Elsa R Flores; Kenneth Y Tsai
• Keywords: Dabrafenib; Trametinib

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.