BRAF inhibitors suppress apoptosis through off-target inhibition of JNK signaling.
Elife
; 2: e00969, 2013 Nov 05.
Article
en En
| MEDLINE
| ID: mdl-24192036
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Oximas
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Sulfonamidas
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Transducción de Señal
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Apoptosis
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Proteínas Proto-Oncogénicas B-raf
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MAP Quinasa Quinasa 4
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Imidazoles
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Indoles
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Elife
Año:
2013
Tipo del documento:
Article
País de afiliación:
Estados Unidos