The transcription cofactor c-JUN mediates phenotype switching and BRAF inhibitor resistance in melanoma
- Ramsdale, R; Jorissen, RN; Li, FZ; Al-Obaidi, S; Ward, T; Sheppard, KE; Bukczynska, PE; Young, RJ; Boyle, SE; Shackleton, M; Bollag, G; Long, GV; Tulchinsky, E; Rizos, H; Pearson, RB; McArthur, GA; Dhillon, AS; Ferrao, PT;
Publication Year 2015, Volume 8, Issue #390, Page ra82
- Journal Title
- Sci Signal
- Publication Type
- Journal Article
- Most patients with BRAF-mutant metastatic melanoma display remarkable but incomplete and short-lived responses to inhibitors of the BRAF kinase or the mitogen-activated protein kinase kinase (MEK), collectively BRAF/MEK inhibitors. We found that inherent resistance to these agents in BRAF(V600)-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 xenografts, 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. Overexpressing c-JUN in drug-naive 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 correlated with a mesenchymal gene signature, implicating c-JUN as a key mediator of the mesenchymal-like phenotype associated with drug resistance.
- WEHI Research Division(s)
- Systems Biology And Personalised Medicine
- PubMed ID
- Publisher's Version
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- Refer to copyright notice on published article.
Creation Date: 2015-09-01 03:55:21Last Modified: 2015-09-02 03:18:32