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Destabilized 3’UTR elements therapeutically degrade ERBB2 mRNA in drug-resistant ERBB2+ cancer models

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...

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Autores principales: Awah, Chidiebere U., Glemaud, Yana, Levine, Fayola, Yang, Kiseok, Ansary, Afrin, Dong, Fu, Ash, Leonard, Zhang, Junfei, Ogunwobi, Olorunseun O.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10287955/
https://www.ncbi.nlm.nih.gov/pubmed/37359373
http://dx.doi.org/10.3389/fgene.2023.1184600
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author Awah, Chidiebere U.
Glemaud, Yana
Levine, Fayola
Yang, Kiseok
Ansary, Afrin
Dong, Fu
Ash, Leonard
Zhang, Junfei
Ogunwobi, Olorunseun O.
author_facet Awah, Chidiebere U.
Glemaud, Yana
Levine, Fayola
Yang, Kiseok
Ansary, Afrin
Dong, Fu
Ash, Leonard
Zhang, Junfei
Ogunwobi, Olorunseun O.
author_sort Awah, Chidiebere U.
collection PubMed
description 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.
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spelling pubmed-102879552023-06-24 Destabilized 3’UTR elements therapeutically degrade ERBB2 mRNA in drug-resistant ERBB2+ cancer models Awah, Chidiebere U. Glemaud, Yana Levine, Fayola Yang, Kiseok Ansary, Afrin Dong, Fu Ash, Leonard Zhang, Junfei Ogunwobi, Olorunseun O. Front Genet Genetics 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. Frontiers Media S.A. 2023-06-09 /pmc/articles/PMC10287955/ /pubmed/37359373 http://dx.doi.org/10.3389/fgene.2023.1184600 Text en Copyright © 2023 Awah, Glemaud, Levine, Yang, Ansary, Dong, Ash, Zhang and Ogunwobi. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Awah, Chidiebere U.
Glemaud, Yana
Levine, Fayola
Yang, Kiseok
Ansary, Afrin
Dong, Fu
Ash, Leonard
Zhang, Junfei
Ogunwobi, Olorunseun O.
Destabilized 3’UTR elements therapeutically degrade ERBB2 mRNA in drug-resistant ERBB2+ cancer models
title Destabilized 3’UTR elements therapeutically degrade ERBB2 mRNA in drug-resistant ERBB2+ cancer models
title_full Destabilized 3’UTR elements therapeutically degrade ERBB2 mRNA in drug-resistant ERBB2+ cancer models
title_fullStr Destabilized 3’UTR elements therapeutically degrade ERBB2 mRNA in drug-resistant ERBB2+ cancer models
title_full_unstemmed Destabilized 3’UTR elements therapeutically degrade ERBB2 mRNA in drug-resistant ERBB2+ cancer models
title_short Destabilized 3’UTR elements therapeutically degrade ERBB2 mRNA in drug-resistant ERBB2+ cancer models
title_sort destabilized 3’utr elements therapeutically degrade erbb2 mrna in drug-resistant erbb2+ cancer models
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10287955/
https://www.ncbi.nlm.nih.gov/pubmed/37359373
http://dx.doi.org/10.3389/fgene.2023.1184600
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