title: BRAF inhibitors suppress apoptosis through off-target inhibition of JNK signaling.
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.
authors.affiliation: Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, United States.
authors.forename: Harina
authors.initials: H
authors.lastname: Vin
authors.forename: Sandra S
authors.initials: SS
authors.lastname: Ojeda
authors.forename: Grace
authors.initials: G
authors.lastname: Ching
authors.forename: Marco L
authors.initials: ML
authors.lastname: Leung
authors.forename: Vida
authors.initials: V
authors.lastname: Chitsazzadeh
authors.forename: David W
authors.initials: DW
authors.lastname: Dwyer
authors.forename: Charles H
authors.initials: CH
authors.lastname: Adelmann
authors.forename: Monica
authors.initials: M
authors.lastname: Restrepo
authors.forename: Kristen N
authors.initials: KN
authors.lastname: Richards
authors.forename: Larissa R
authors.initials: LR
authors.lastname: Stewart
authors.forename: Lili
authors.initials: L
authors.lastname: Du
authors.forename: Scarlett B
authors.initials: SB
authors.lastname: Ferguson
authors.forename: Deepavali
authors.initials: D
authors.lastname: Chakravarti
authors.forename: Karin
authors.initials: K
authors.lastname: Ehrenreiter
authors.forename: Manuela
authors.initials: M
authors.lastname: Baccarini
authors.forename: Rosamaria
authors.initials: R
authors.lastname: Ruggieri
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Curry
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Kim
authors.forename: Ana M
authors.initials: AM
authors.lastname: Ciurea
authors.forename: Madeleine
authors.initials: M
authors.lastname: Duvic
authors.forename: Victor G
authors.initials: VG
authors.lastname: Prieto
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Ullrich
authors.forename: Kevin N
authors.initials: KN
authors.lastname: Dalby
authors.forename: Elsa R
authors.initials: ER
authors.lastname: Flores
authors.forename: Kenneth Y
authors.initials: KY
authors.lastname: Tsai
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008812:Mice, Hairless; D010091:Oximes / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology*; D000077484:Vemurafenib
chemical_list: D007093:Imidazoles; D007211:Indoles; D010091:Oximes; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048670:MAP Kinase Kinase 4; C561627:dabrafenib
keywords: apoptosis; cancer; melanoma; protein kinase; squamous cell carcinoma; targeted therapy