Epigenetic Drugs Modulate Long Noncoding Rnas Expression In Braf Inhibitor-Resistant Melanoma

Emergence of drug resistance is the major cause of failure of BRAF inhibitors (BRAFi) treatment in cutaneous melanoma (CM). Epigenetic modifications are known to physiologically trigger massive modifications in cellular commitment and several studies report a correlation between the drug-resistant phenotype and epigenetic alterations of tumor cells. In this setting, long noncoding RNAs (lncRNAs) represent a class of gene regulators acting at epigenetic, transcriptional and post-transcriptional level. Several studies have implicated lncRNAs in chemoresistance through their ability to impair cell cycle arrest and apoptosis, but also to induce and modulate epithelial-mesenchymal transition and cell adhesion-associated signaling pathways. LncRNAs interact with histone modifying complexes and/or DNA methyltransferases, being also targets of these epigenetic mediators. Furthermore, epigenetic drugs have been recently identified as modulators for lncRNAs function as well as their related targeting signals. Starting from these evidences, we asked the question whether epigenetic drugs could differentially affect the survival of BRAFi-resistant (VR) and -sensitive CM cells, investigating the mechanistic network involved, with a specific focus on the role of lncRNA. A panel of BRAFi-sensitive and VR CM cell lines was treated with the FDA-approved HDAC inhibitor vorinostat (SAHA). FACS analysis of annexin V-FITC/propidium iodide stained cells showed that SAHA cytotoxic activity was more pronounced on VR CM cells than on their parental counterparts. RNA-Seq analysis revealed that a large number of differentially expressed lncRNAs was modulated in VR CM cells treated with SAHA. Intriguingly, the expression of several VR up-regulated lncRNAs was decreased to levels similar to those observed in the matched parental cells. Functional analysis indicated these lncRNAs were statistically enriched in pathways involving cellular growth and proliferation, but also cellular assembly and organization. Though additional studies are required, epigenetic modulation of VR-associated lncRNAs promises to have significant therapeutic potential to restore BRAFi sensivity in CM, being concomitantly effective in killing VR cells as monotherapy. Based on our preliminary data, we could anticipate that the combined use of epigenetic and targeted drugs would increase therapeutic efficacy in CM patients relapsing to BRAFi. Citation Format: Barbara Montico, Giorgio Giurato, Katy Mastorci, Aurora Rizzo, Maria Ravo, Francesca Rizzo, Alessandro Weisz, Riccardo Dolcetti, Francesca Colizzi, Luca Sigalotti, Elisabetta Fratta. Epigenetic drugs modulate long noncoding RNAs expression in BRAF inhibitor-resistant melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1196. doi:10.1158/1538-7445.AM2017-1196