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

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
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 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.
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