title: Melanoma Expressed-CD70 Is Regulated by RhoA and MAPK Pathways without Affecting Vemurafenib Treatment Activity.
abstract: CD70 is a costimulatory molecule member of the Tumor Necrosis Factor family that is expressed on activated immune cells. Its ectopic expression has been described in several types of cancer cells including lymphomas, renal cell carcinomas and glioblastomas. We have recently described its expression in a part of tumor cells from the vast majority of melanoma biopsies and human melanoma cell lines, and found that CD70 expression decreased over time as the disease progressed. Here, we show that RhoA, BRAF and Mitogen Activating Protein Kinase pathways are involved in the positive transcriptional regulation of CD70 expression in melanomas. Interestingly, the clinical inhibitor of the common BRAF V600E/D variants, Vemurafenib (PLX-4032), which is currently used to treat melanoma patients with BRAF V600E/D-mutated metastatic melanomas, decreased CD70 expression in human CD70+ melanoma cell lines. This decrease was seen in melanoma cells both with and without the BRAFV600E/D mutation, although was less efficient in those lacking the mutation. But interestingly, by silencing CD70 in CD70+ melanoma cell lines we show that PLX-4032-induced melanoma cell killing and its inhibitory effect on MAPK pathway activation are unaffected by CD70 expression. Consequently, our work demonstrates that CD70 ectopic expression in melanomas is not a valuable biomarker to predict tumor cells sensitivity to BRAF V600 inhibitors.
authors.affiliation: INSERM UMR 1037, CRCT, Toulouse FR-31037, France.|Université Paul Sabatier, Toulouse FR-31062, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Pich
authors.affiliation: INSERM UMR 1037, CRCT, Toulouse FR-31037, France.|Université Paul Sabatier, Toulouse FR-31062, France.
authors.forename: Iotefa
authors.initials: I
authors.lastname: Teiti
authors.affiliation: INSERM UMR 1037, CRCT, Toulouse FR-31037, France.|Université Paul Sabatier, Toulouse FR-31062, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Sarrabayrouse
authors.affiliation: NeoVirTech, Institut des Sciences du vivant, Toulouse FR-31106, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Gallardo
authors.affiliation: INSERM UMR 1037, CRCT, Toulouse FR-31037, France.|Université Paul Sabatier, Toulouse FR-31062, France.
authors.forename: Rémi
authors.initials: R
authors.lastname: Gence
authors.affiliation: Université Paul Sabatier, Toulouse FR-31062, France.|INSERM U1220, IRSD, Toulouse FR-31024, France.
authors.forename: Anne-Françoise
authors.initials: AF
authors.lastname: Tilkin-Mariamé
mesh_terms: D053282:CD27 Ligand / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D012878:Skin Neoplasms; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D014158:Transcription, Genetic / Q000187:drug effects; D000077484:Vemurafenib; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*; D000096142:Cutaneous Malignant Melanoma
chemical_list: D053282:CD27 Ligand; D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020742:rhoA GTP-Binding Protein
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