1. Selective targeting of MYC mRNA by stabilized antisense oligonucleotides
- Author
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Gill, Taylor, Wang, Haichuan, Bandaru, Raj, Lawlor, Matthew, Lu, Chenyue, Nieman, Linda T, Tao, Junyan, Zhang, Yixian, Anderson, Daniel G, Ting, David T, Chen, Xin, Bradner, James E, and Ott, Christopher J
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Biological Sciences ,Rare Diseases ,Genetics ,Biotechnology ,Liver Disease ,Orphan Drug ,Cancer ,Digestive Diseases ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Animals ,Apoptosis ,Carcinoma ,Hepatocellular ,Cell Proliferation ,Female ,Humans ,Liver Neoplasms ,Mice ,Mice ,Inbred C57BL ,Oligonucleotides ,Antisense ,Proto-Oncogene Proteins c-myc ,RNA Stability ,Tumor Cells ,Cultured ,Xenograft Model Antitumor Assays ,Clinical Sciences ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
MYC is a prolific proto-oncogene driving the malignant behaviors of numerous common cancers, yet potent and selective cell-permeable inhibitors of MYC remain elusive. In order to ultimately realize the goal of therapeutic MYC inhibition in cancer, we have initiated discovery chemistry efforts aimed at inhibiting MYC translation. Here we describe a series of conformationally stabilized synthetic antisense oligonucleotides designed to target MYC mRNA (MYCASOs). To support bioactivity, we designed and synthesized this focused library of MYCASOs incorporating locked nucleic acid (LNA) bases at the 5'- and 3'-ends, a phosphorothioate backbone, and internal DNA bases. Treatment of MYC-expressing cancer cells with MYCASOs leads to a potent decrease in MYC mRNA and protein levels. Cleaved MYC mRNA in MYCASO-treated cells is detected with a sensitive 5' Rapid Amplification of cDNA Ends (RACE) assay. MYCASO treatment of cancer cell lines leads to significant inhibition of cellular proliferation while specifically perturbing MYC-driven gene expression signatures. In a MYC-induced model of hepatocellular carcinoma, MYCASO treatment decreases MYC protein levels within tumors, decreases tumor burden, and improves overall survival. MYCASOs represent a new chemical tool for in vitro and in vivo modulation of MYC activity, and promising therapeutic agents for MYC-addicted tumors.
- Published
- 2021