SPRED1 is a negative regulator of the MAPK pathway frequently deleted in human melanoma.,Through in vivo modeling in zebrafish and mechanistic analyses in human cell lines, Ablain et al. demonstrate that SPRED1 inactivation confers resistance to targeted inhibition of V600 mutant BRAF, the most common driver of melanoma.,Functional evaluation of genetic lesions can discover a role in cancer initiation and progression and help develop novel therapeutic strategies.,We previously identified the negative MAPK regulator SPRED1 as a novel tumor suppressor in KIT-driven melanoma.,Here, we show that SPRED1 is also frequently deleted in human melanoma driven by mutant BRAF.,We found that SPRED1 inactivation in human melanoma cell lines and primary zebrafish melanoma conferred resistance to BRAFV600E inhibition in vitro and in vivo.,Mechanistically, SPRED1 loss promoted melanoma cell proliferation under mutant BRAF inhibition by reactivating MAPK activity.,Consistently, biallelic deletion of SPRED1 was observed in a patient whose melanoma acquired resistance to MAPK-targeted therapy.,These studies combining work in human cells and in vivo modeling in zebrafish demonstrate a new mechanism of resistance to BRAFV600E inhibition in melanoma.
The development and progression of melanoma have been attributed to independent or combined genetic and epigenetic events.,There has been remarkable progress in understanding melanoma pathogenesis in terms of genetic alterations.,However, recent studies have revealed a complex involvement of epigenetic mechanisms in the regulation of gene expression, including methylation, chromatin modification and remodeling, and the diverse activities of non-coding RNAs.,The roles of gene methylation and miRNAs have been relatively well studied in melanoma, but other studies have shown that changes in chromatin status and in the differential expression of long non-coding RNAs can lead to altered regulation of key genes.,Taken together, they affect the functioning of signaling pathways that influence each other, intersect, and form networks in which local perturbations disturb the activity of the whole system.,Here, we focus on how epigenetic events intertwine with these pathways and contribute to the molecular pathogenesis of melanoma.