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
AUTHORS (25)
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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CITATIONS (71)
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