Research ArticleCancer

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

Sci. Signal.  18 Aug 2015:
Vol. 8, Issue 390, pp. ra82
DOI: 10.1126/scisignal.aab1111

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Inhibiting two MAPKs is better than one

Mitogen-activated protein kinase (MAPK) pathways, such as the ERK and JNK pathways, mediate critical cellular processes, such as survival, stress responses, and proliferation. These pathways can be hijacked by cancer cells, leading to uncontrolled cell division and metastasis. Many melanoma patients have activating mutations in an upstream kinase, BRAF, in the ERK pathway, but inhibitors of BRAF only produce short-term improvement. Using panels of melanoma cell lines and BRAF inhibitor–treated patient samples, Ramsdale et al. found that increased abundance of the transcription cofactor c-JUN, which is activated by the JNK pathway, mediated both inherent and adaptive resistance to BRAF inhibitors and contributed to metastatic potential. Blocking c-JUN abundance or its activation by the kinase JNK enhanced the efficacy of BRAF inhibitors against melanoma cells. Thus, targeting both MAPK pathways may overcome resistance to treatment with only inhibitors of the ERK pathway.

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 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 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.

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