Frontiers in Genetics (Jun 2023)

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

  • Chidiebere U. Awah,
  • Chidiebere U. Awah,
  • Yana Glemaud,
  • Fayola Levine,
  • Fayola Levine,
  • Kiseok Yang,
  • Afrin Ansary,
  • Fu Dong,
  • Leonard Ash,
  • Junfei Zhang,
  • Olorunseun O. Ogunwobi,
  • Olorunseun O. Ogunwobi

DOI
https://doi.org/10.3389/fgene.2023.1184600
Journal volume & issue
Vol. 14

Abstract

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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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