title: Detrimental effects of melanocortin-1 receptor (MC1R) variants on the clinical outcomes of BRAF V600 metastatic melanoma patients treated with BRAF inhibitors.
abstract: Melanocortin-1 receptor (MC1R) plays a key role in skin pigmentation, and its variants are linked with a higher melanoma risk. The influence of MC1R variants on the outcomes of patients with metastatic melanoma (MM) treated with BRAF inhibitors (BRAFi) is unknown. We studied the MC1R status in a cohort of 53 consecutive BRAF-mutated patients with MM treated with BRAFi. We also evaluated the effect of vemurafenib in fourV600BRAF melanoma cell lines with/without MC1R variants. We found a significant correlation between the presence of MC1R variants and worse outcomes in terms of both overall response rate (ORR; 59% versus 95%, P = 0.011 univariate, P = 0.028 multivariate analysis) and progression-free survival (PFS) shorter than 6 months (72% versus 33%, P = 0.012 univariate, P = 0.027 multivariate analysis). No difference in overall survival (OS) was reported, probably due to subsequent treatments. Data in vitro showed a significant different phosphorylation of Erk1/2 and p38 MAPK during treatment, associated with a greater increase in vemurafenib IC50 in MC1R variant cell lines.
authors.affiliation: Medical Oncology Department, National Cancer Research Centre 'Giovanni Paolo II', Bari, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Guida
authors.affiliation: Medical Oncology Department, National Cancer Research Centre 'Giovanni Paolo II', Bari, Italy.
authors.forename: Sabino
authors.initials: S
authors.lastname: Strippoli
authors.affiliation: Medical Oncology Department, National Cancer Research Centre 'Giovanni Paolo II', Bari, Italy.|Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari, Bari, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Ferretta
authors.affiliation: Department of Biomedical Sciences and Human Oncology, University of Bari, Bari, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Bartolomeo
authors.affiliation: Experimental Pharmacology Laboratory, National Cancer Research Centre 'Giovanni Paolo II', Bari, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Porcelli
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari, Bari, Italy.
authors.forename: Immacolata
authors.initials: I
authors.lastname: Maida
authors.affiliation: Experimental Pharmacology Laboratory, National Cancer Research Centre 'Giovanni Paolo II', Bari, Italy.
authors.forename: Amalia
authors.initials: A
authors.lastname: Azzariti
authors.affiliation: Molecular Genetics Laboratory and Radiology, National Cancer Research Centre 'Giovanni Paolo II', Bari, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Tommasi
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari, Bari, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Grieco
authors.affiliation: Dermatology Unit, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Guida
authors.affiliation: Medical Oncology Department, National Cancer Research Centre 'Giovanni Paolo II', Bari, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Albano
authors.affiliation: Medical Oncology Department, National Cancer Research Centre 'Giovanni Paolo II', Bari, Italy.
authors.forename: Vito
authors.initials: V
authors.lastname: Lorusso
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari, Bari, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Guida
mesh_terms: D001859:Bone Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000556:secondary*; D049109:Cell Proliferation; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000556:secondary*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000556:secondary*; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics*; D015996:Survival Rate; D014407:Tumor Cells, Cultured
chemical_list: D047428:Protein Kinase Inhibitors; D044102:Receptor, Melanocortin, Type 1; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF inhibitors; Melanocortin-1 receptor; metastatic melanoma; predictive biomarkers