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

Linda Vidarsdottir,Johan Hansson,Sakari Kauppinen,Alireza Azimi,Suzanne Egyházi Brage,Aldwin Suryo Rahmanto,Ingibjorg Sigvaldadottir,Per Johnsson,Christian Ingvar,Dan Grandér,Göran Jönsson,Ishani Das,Rainer Tuominen,Andreas Petri,Marianne Frostvik Stolt,Katja Pokrovskaja Tamm,Olle Sangfelt,Håkan Olsson

doi:10.1038/s41598-021-89389-9

Linda Vidarsdottir, Johan Hansson + Show 16 more

Open Access

https://doi.org/10.1038/s41598-021-89389-9

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Abstract

BRAF inhibitors (BRAFi) selectively target oncogenic BRAFV600E/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.

Highlights

Cutaneous malignant melanoma is a molecularly diverse disease, approximately 50% carry activating mutations in the serine/threonine protein kinase BRAF
We set out to investigate if PTENP1-AS was involved in this process through transcriptional suppression of PTEN
We explored if the resistant A375PR1 cells could be sensitized to BRAF inhibitors (BRAFi) by targeting the PTENP1-AS transcript

Summary

Introduction

Cutaneous malignant melanoma is a molecularly diverse disease, approximately 50% carry activating mutations in the serine/threonine protein kinase BRAF. In recent years there has been a growing understanding of the underlying molecular mechanisms involved in acquired BRAFi r esistance[4,5] and activation of the PI3K/AKT pathway due to loss of PTEN has been found to contribute to this p rocess[6]. Our aim was to characterize the impact of PTENP1-AS on clinical outcome in stage III melanoma and BRAFi treatment efficacy. We observe that the expression of PTENP1-AS is induced in BRAFi resistant sublines in relation to the parental sensitive cell line. This coincides with transcriptional suppression of PTEN, likely through the recruitment of EZH2 and subsequent formation of H3K27me[3] at the PTEN promoter. Our study provides insights into the involvement of PTENP1-AS in resistance to BRAFi treatment

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