title: The c-Jun/RHOB/AKT pathway confers resistance of BRAF-mutant melanoma cells to MAPK inhibitors.
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.
authors.affiliation: Inserm, UMR 1037-CRCT, Toulouse, France.|Université Paul Sabatier, Toulouse, France.|Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse-Oncopole, Laboratory of Medical Biology and Oncogenetics, Toulouse, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Delmas
authors.affiliation: Inserm, UMR 1037-CRCT, Toulouse, France.|Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse-Oncopole, Laboratory of Medical Biology and Oncogenetics, Toulouse, France.
authors.forename: Julia
authors.initials: J
authors.lastname: Cherier
authors.affiliation: Inserm, UMR 1037-CRCT, Toulouse, France.|Université Paul Sabatier, Toulouse, France.|Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse-Oncopole, Laboratory of Medical Biology and Oncogenetics, Toulouse, France.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Pohorecka
authors.affiliation: Inserm, UMR 1037-CRCT, Toulouse, France.|Université Paul Sabatier, Toulouse, France.|Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse-Oncopole, Laboratory of Medical Biology and Oncogenetics, Toulouse, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Medale-Giamarchi
authors.affiliation: Inserm, UMR 1037-CRCT, Toulouse, France.|Université Paul Sabatier, Toulouse, France.|Centre Hospitalo-Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse-Oncopole, Department of Dermatology, Toulouse, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Meyer
authors.affiliation: Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse-Oncopole, Laboratory of Medical Biology and Oncogenetics, Toulouse, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Casanova
authors.affiliation: Inserm, UMR 1037-CRCT, Toulouse, France.|Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse-Oncopole, Laboratory of Medical Biology and Oncogenetics, Toulouse, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Sordet
authors.affiliation: Inserm, UMR 1037-CRCT, Toulouse, France.|Centre Hospitalo-Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse-Oncopole, Department of Pathology, Toulouse, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Lamant
authors.affiliation: Scientific Partnerships, Roche SAS, Boulogne Billancourt, France.
authors.forename: Ariel
authors.initials: A
authors.lastname: Savina
authors.affiliation: Inserm, UMR 1037-CRCT, Toulouse, France.|Université Paul Sabatier, Toulouse, France.|Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse-Oncopole, Laboratory of Medical Biology and Oncogenetics, Toulouse, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Pradines
authors.affiliation: Inserm, UMR 1037-CRCT, Toulouse, France.|Université Paul Sabatier, Toulouse, France.|Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse-Oncopole, Laboratory of Medical Biology and Oncogenetics, Toulouse, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Favre
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D000077484:Vemurafenib; D020743:rhoB GTP-Binding Protein / Q000378:metabolism
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D020743:rhoB GTP-Binding Protein
keywords: AKT; RHOB; melanoma; resistance; vemurafenib