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BRAF inhibitors (BRAFi) selectively target oncogenic BRAF V600E/K  and are effective in 80% of advanced cutaneous malignant melanoma cases carrying the V600 mutation. However, the development of drug resistance limits their clinical efficacy. Better characterization of the underlying molecular processes is needed to further improve treatments. We previously demonstrated that transcription of  PTEN  is negatively regulated by the  PTEN  pseudogene antisense RNA,  PTENP1-AS , and here we investigated the impact of this transcript on clinical outcome and BRAFi resistance in melanoma. We observed that increased expression levels of  PTENP1-AS  in BRAFi resistant cells associated with enrichment of EZH2 and H3K27me3 at the  PTEN  promoter, consequently reducing the expression levels of  PTEN . Further, we showed that targeting of the  PTENP1-AS  transcript sensitized resistant cells to BRAFi treatment and that high expression of  PTENP1-AS  in stage III melanoma correlated with poor survival. Collectively, the data presented here show that  PTENP1-AS  is a promising target for re-sensitizing cells to BRAFi and also a possible prognostic marker for clinical outcome in stage III melanoma.

PTENP1-AS contributes to BRAF inhibitor resistance and is associated with adverse clinical outcome in stage III melanoma