The transcription cofactor c-JUN mediates phenotype switching and BRAF inhibitor resistance in melanoma

Rachel Ramsdale, Robert N. Jorissen, Frederic Z. Li, Sheren Al-Obaidi, Teresa Ward, Karen E. Sheppard, Patricia E. Bukczynska, Richard J. Young, Samantha E. Boyle, Mark Shackleton, Gideon Bollag, Georgina V. Long, Eugene Tulchinsky, Helen Rizos, Richard B. Pearson, Grant A. McArthur, Amardeep S. Dhillon, Petranel T. Ferrao

Research output: Contribution to journalArticlepeer-review

61 Citations (Scopus)

Abstract

Most patients with BRAF-mutant metastatic melanoma display remarkable but incomplete and short-lived responses to inhibitors of the BRAF kinase or the mito gen-activated protein kinase kinase (MEK), collectively BRAF/MEK inhibitors. We found that inherent resistance to these agents in BRAFV600-mutant melanoma cell lines was associated with high abundance of c-JUN and characteristics of a mesenchymal-like phenotype. Early drug adaptation in drug-sensitive cell lines grown in culture or as xeno grafts, and in patient samples during therapy, was consistently characterized by down-regulation of SPROUTY4 (a negative feedback regulator of receptor tyrosine kinases and the BRAF-MEK signaling pathway), increased expression of JUN and reduced expression of LEF1. This coincided with a switch in phenotype that resembled an epithelial-mesenchymal transition (EMT). In cultured cells, these BRAF inhibitor-induced changes were reversed upon removal of the drug. Knockdown of SPROUTY4 was sufficient to increase the abundance of c-JUN in the absence of drug treatment. Over expressing c-JUN in drug-naïve melanoma cells induced similar EMT-like phenotypic changes to BRAF inhibitor treatment, whereas knocking down JUN abrogated the BRAF inhibitor-induced early adaptive changes associated with resistance and enhanced cell death. Combining the BRAF inhibitor with an inhibitor of c-JUN amino-terminal kinase (JNK) reduced c-JUN phosphorylation, decreased cell migration, and increased cell death in melanoma cells. Gene expression data from a panel of melanoma cell lines and a patient cohort showed that JUN expression correlatedwith a mesenchymal gene signature, implicating c-JUN as a key mediator of the mesenchymal-like phenotype associated with drug resistance.

Original languageEnglish
Pages (from-to)ra82
JournalScience Signaling
Volume8
Issue number390
DOIs
Publication statusPublished - Aug 18 2015
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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