Selective targeting of MYC mRNA by stabilized antisense oligonucleotides.

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.

• Authors: Taylor Gill, Haichuan Wang, Raj Bandaru, Matthew Lawlor, Chenyue Lu, Linda T Nieman, Junyan Tao, Yixian Zhang, Daniel G Anderson, David T Ting, Xin Chen, James E Bradner, Christopher J Ott
• Journal: Oncogene (Oncogene) Vol. 40 Issue 47 Pg. 6527-6539 (11 2021) ISSN: 1476-5594 [Electronic] England
• PMID: 34650218 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• MYC protein, human
• Oligonucleotides, Antisense
• Proto-Oncogene Proteins c-myc

Topics

• Animals
• Apoptosis
• Carcinoma, Hepatocellular (drug therapy, genetics, pathology)
• Cell Proliferation
• Female
• Humans
• Liver Neoplasms (drug therapy, genetics, pathology)
• Mice
• Mice, Inbred C57BL
• Oligonucleotides, Antisense (chemistry, pharmacology)
• Proto-Oncogene Proteins c-myc (antagonists & inhibitors, genetics)
• RNA Stability
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays