2. Academic Validation
  3. Mammalian Target of Rapamycin Inhibition Enhances Delivery and Activity of Antisense Oligonucleotides in Uveal Melanoma Cells

Mammalian Target of Rapamycin Inhibition Enhances Delivery and Activity of Antisense Oligonucleotides in Uveal Melanoma Cells

  • Nucleic Acid Ther. 2023 Jun 30. doi: 10.1089/nat.2023.0008.
Shanna Dewaele 1 2 3,  Louis Delhaye 1 2 3 4,  Boel De Paepe 5,  Bram Bogaert 2 6,  Ramiro Martinez 1 2 3,  Jasper Anckaert 1 2 3,  Nurten Yigit 1 2 3,  Justine Nuytens 1 2 3,  Rudy Van Coster 5,  Sven Eyckerman 2 3 4,  Koen Raemdonck 2 6,  Pieter Mestdagh 1 2 3
Affiliations

Affiliations

  • 1 OncoRNALab, Center for Medical Genetics (CMGG), Ghent University, Ghent, Belgium.
  • 2 Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium.
  • 3 Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
  • 4 Center for Medical Biotechnology, VIB-Ghent University, Ghent, Belgium.
  • 5 Division of Pediatric Neurology and Metabolism, Department of Pediatrics, Ghent University Hospital, Ghent, Belgium.
  • 6 Laboratory for General Biochemistry and Physical Pharmacy, Ghent University, Ghent, Belgium.
PMID: 37389884 DOI: 10.1089/nat.2023.0008
Abstract

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Owing to a lack of effective treatments, patients with metastatic disease have a median survival time of 6-12 months. We recently demonstrated that the Survival Associated Mitochondrial Melanoma Specific Oncogenic Non-coding RNA (SAMMSON) is essential for UM 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 mammalian target of rapamycin (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.

Keywords

ASO; combination therapy; compound; lipid nanoparticle; oncology; siRNA.

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