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

Elife. 2013 Nov 5;2:e00969. doi: 10.7554/eLife.00969.


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:

Keywords: apoptosis; cancer; melanoma; protein kinase; squamous cell carcinoma; targeted therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Humans
  • Imidazoles / pharmacology*
  • Indoles / pharmacology*
  • MAP Kinase Kinase 4 / antagonists & inhibitors*
  • MAP Kinase Kinase 4 / metabolism
  • Mice
  • Mice, Hairless
  • Oximes / pharmacology*
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • Signal Transduction / drug effects*
  • Sulfonamides / pharmacology*
  • Vemurafenib


  • Imidazoles
  • Indoles
  • Oximes
  • Sulfonamides
  • Vemurafenib
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • MAP Kinase Kinase 4
  • dabrafenib