The transcription cofactor c-JUN mediates phenotype switching and BRAF inhibitor resistance in melanoma - PubMed (original) (raw)

. 2015 Aug 18;8(390):ra82.

doi: 10.1126/scisignal.aab1111.

Robert N Jorissen 2, Frederic Z Li 3, Sheren Al-Obaidi 1, Teresa Ward 1, Karen E Sheppard 4, Patricia E Bukczynska 5, Richard J Young 5, Samantha E Boyle 6, Mark Shackleton 7, Gideon Bollag 8, Georgina V Long 9, Eugene Tulchinsky 10, Helen Rizos 11, Richard B Pearson 12, Grant A McArthur 13, Amardeep S Dhillon 14, Petranel T Ferrao 15

Affiliations

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

Rachel Ramsdale et al. Sci Signal. 2015.

Abstract

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-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 correlated with a mesenchymal gene signature, implicating c-JUN as a key mediator of the mesenchymal-like phenotype associated with drug resistance.

Copyright © 2015, American Association for the Advancement of Science.

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