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

Harina Vin, Sandra S. Ojeda, Grace Ching, Marco L. Leung, Vida Chitsazzadeh, David W. Dwyer, Charles H. Adelmann, Monica Restrepo, Kristen N. Richards, Larissa R. Stewart, Lili Du, Scarlett B. Ferguson, Deepavali Chakravarti, Karin Ehrenreiter, Manuela Baccarini, Rosamaria Ruggieri, Jonathan L. Curry, Kevin B. Kim, Ana M. Ciurea, Madeleine DuvicVictor G. Prieto, Stephen E. Ullrich, Kevin N. Dalby, Elsa R. Flores, Kenneth Y. Tsai

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

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.

Original languageEnglish (US)
Article numbere00969
JournaleLife
Volume2013
Issue number2
DOIs
StatePublished - Nov 5 2013

ASJC Scopus subject areas

  • General Neuroscience
  • General Immunology and Microbiology
  • General Biochemistry, Genetics and Molecular Biology

MD Anderson CCSG core facilities

  • Advanced Technology Genomics Core
  • Flow Cytometry and Cellular Imaging Facility
  • Research Animal Support Facility

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