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- Title
Destabilized 3’UTR elements therapeutically degrade ERBB2 mRNA in drug-resistant ERBB2+ cancer models.
- Authors
Awah, Chidiebere U.; Glemaud, Yana; Levine, Fayola; Kiseok Yang; Ansary, Afrin; Fu Dong; Ash, Leonard; Junfei Zhang; Ogunwobi, Olorunseun O.
- Abstract
Breast, lung, and colorectal cancer resistance to molecular targeted therapy is a major challenge that unfavorably impacts clinical outcomes leading to hundreds of thousands of deaths annually. In ERBB2+ cancers regardless of the tissue of origin, many ERBB2+ cancers are resistant to ERBB2-targeted therapy. We discovered that ERBB2+ cancer cells are enriched with poly U sequences on their 3’UTR which are mRNA-stabilizing sequences. We developed a novel technology, in which we engineered these ERBB2 mRNA-stabilizing sequences to unstable forms that successfully overwrote and outcompeted the endogenous ERBB2 mRNA-encoded message and degraded ERBB2 transcripts which led to the loss of the protein across multiple cancer cell types both in the wildtype and drug-resistance settings in vitro and in vivo, offering a unique safe novel modality to control ERBB2 mRNA and other pervasive oncogenic signals where current targeted therapies fail.
- Subjects
BREAST; MESSENGER RNA; COLORECTAL cancer; CANCER cells; TREATMENT effectiveness
- Publication
Frontiers in Genetics, 2023, p1
- ISSN
1664-8021
- Publication type
Article
- DOI
10.3389/fgene.2023.1184600