mTOR inhibition enhances delivery and activity of antisense oligonucleotides in uveal melanoma cells

Abstract

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Due to a lack of effective treatments, patients with metastatic disease have a median survival time of 6-12 months. We recently demonstrated that the SAMMSON long non-coding RNA (lncRNA) is essential for uveal melanoma cell survival and that antisense oligonucleotide (ASO)-mediated silencing of SAMMSON impaired cell viability and tumor growth in vitro and in vivo. By screening a library of 2911 clinical stage compounds, we identified the mTOR inhibitor GDC-0349 to synergize with SAMMSON inhibition in UM. Mechanistic studies revealed that mTOR inhibition enhanced uptake and reduced lysosomal accumulation of lipid complexed SAMMSON ASOs, improving SAMMSON knockdown and further decreasing UM cell viability. We found mTOR inhibition to also enhance target knockdown in other cancer cell lines as well as normal cells when combined with lipid nanoparticle complexed or encapsulated ASOs or small interfering RNAs (siRNAs). Our results are relevant to nucleic acid treatment in general and highlight the potential of mTOR inhibition to enhance ASO and siRNA mediated target knockdown.

Discovery platforms for RNA therapeutics

“…In this project, over 20.000 cancer samples, spanning 33 cancer types, have been analyzed by genomics, epigenomics, transcriptomics, and proteomics, together with matched healthy samples. Numerous novel targets, including RNA therapeu7cs, have been discovered by this approach, as, for example, a ASO to silence the oncogenic lncRNA SAMMSON for the therapy of melanoma (Dewaele et al, 2023;Dewaele et al, 2022).…”