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: squamous cell carcinoma; Proto-Oncogene Proteins B-raf; CYCLE ARREST; Indoles; Mouse; QH301-705.5; MAP Kinase Kinase 4; Science; Apoptosis; GAMMA-RADIATION; H9C2 CARDIOMYOBLAST CELLS; FACTOR EXPRESSION; Mice; 03 medical and health sciences; Oximes; melanoma; METASTATIC MELANOMA; cancer; Animals; Humans; Biology (General); TUMOR PROGRESSION; Human Biology and Medicine; 106022 Mikrobiologie; Mice, Hairless; Sulfonamides; 0303 health sciences; MOLECULAR-CLONING; Q; apoptosis; R; Imidazoles; protein kinase; KINASE INHIBITOR; targeted therapy; 3. Good health; RAS MUTATIONS; Vemurafenib; 106022 Microbiology; Medicine; Human; ACQUIRED-RESISTANCE; Signal Transduction

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.