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Oncotarget. 2015 Jun 20;6(17):15250-64.

The c-Jun/RHOB/AKT pathway confers resistance of BRAF-mutant melanoma cells to MAPK inhibitors.

Author information

1
Inserm, UMR 1037-CRCT, Toulouse, France.
2
Université Paul Sabatier, Toulouse, France.
3
Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse-Oncopole, Laboratory of Medical Biology and Oncogenetics, Toulouse, France.
4
Centre Hospitalo-Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse-Oncopole, Department of Dermatology, Toulouse, France.
5
Centre Hospitalo-Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse-Oncopole, Department of Pathology, Toulouse, France.
6
Scientific Partnerships, Roche SAS, Boulogne Billancourt, France.

Abstract

The response of BRAF-mutant melanoma patients to BRAF inhibitors is dramatically impaired by secondary resistances and rapid relapse. So far, the molecular mechanisms driving these resistances are not completely understood. Here, we show that, in BRAF-mutant melanoma cells, inhibition of BRAF or its target MEK induces RHOB expression by a mechanism that depends on the transcription factor c-Jun. In those cells, RHOB deficiency causes hypersensitivity to BRAF and MEK inhibitors-induced apoptosis. Supporting these results, loss of RHOB expression in metastatic melanoma tissues is associated with an increased progression-free survival of BRAF-mutant patients treated with vemurafenib. Following BRAF inhibition, RHOB activates AKT whose inhibition causes hypersensitivity of BRAF-mutant melanoma cells to BRAF inhibitors. In mice, AKT inhibition synergizes with vemurafenib to block tumor growth of BRAF-mutant metastatic melanoma. Our findings reveal that BRAF inhibition activates a c-Jun/RHOB/AKT pathway that promotes tumor cell survival and further support a role of this pathway in the resistance of melanoma to vemurafenib. Our data also highlight the importance of using RHOB tumor levels as a biomarker to predict vemurafenib patient's response and to select those that would benefit of the combination with AKT inhibitors.

KEYWORDS:

AKT; RHOB; melanoma; resistance; vemurafenib

PMID:
26098773
PMCID:
PMC4558149
DOI:
10.18632/oncotarget.3888
[Indexed for MEDLINE]
Free PMC Article

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