Detrimental effects of melanocortin‐1 receptor (MC1R) variants on the clinical outcomes of BRAF V600 metastatic melanoma patients treated with BRAF inhibitors

Summary Melanocortin‐1 receptor ( MC 1R) plays a key role in skin pigmentation, and its variants are linked with a higher melanoma risk. The influence of MC 1R variants on the outcomes of patients with metastatic melanoma ( MM ) treated with BRAF inhibitors ( BRAF i) is unknown. We studied the MC 1R status in a cohort of 53 consecutive BRAF ‐mutated patients with MM treated with BRAF i. We also evaluated the effect of vemurafenib in four V600 BRAF melanoma cell lines with/without MC 1R variants. We found a significant correlation between the presence of MC 1R 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 IC 50 in MC 1R variant cell lines.