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

Chidiebere U Awah1,2, Yana Glemaud1, Fayola Levine1,2

  • 1Department of Biological Sciences, Hunter College of The City University of New York, New York City, NY, United States.

Frontiers in Genetics
|June 26, 2023
PubMed

Insights

Researchers developed a novel therapy targeting ERBB2 mRNA in resistant cancers. This approach degrades ERBB2 transcripts, reducing the oncogenic protein and offering a new treatment modality for difficult-to-treat ERBB2+ cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biotechnology

Background:

  • Molecular targeted therapies face challenges with cancer resistance, particularly in ERBB2+ cancers.
  • ERBB2+ cancers often exhibit resistance to existing ERBB2-targeted treatments, leading to poor clinical outcomes.

Purpose of the Study:

  • To investigate the role of 3' untranslated region (3'UTR) poly U sequences in ERBB2 mRNA stabilization.
  • To develop a novel therapeutic strategy to overcome ERBB2-targeted therapy resistance by degrading ERBB2 mRNA.

Main Methods:

  • Engineered ERBB2 mRNA 3'UTR sequences to create unstable forms.
  • Utilized these engineered sequences to outcompete and degrade endogenous ERBB2 mRNA.
  • Evaluated the efficacy of this approach in wildtype and drug-resistant cancer cells in vitro and in vivo.

Main Results:

  • The engineered sequences successfully degraded ERBB2 transcripts.
  • This degradation led to a significant loss of ERBB2 protein in various cancer cell types.
  • The approach demonstrated effectiveness in both standard and drug-resistant cancer models.

Conclusions:

  • Targeting ERBB2 mRNA stability offers a novel therapeutic modality for ERBB2+ cancers.
  • This strategy effectively reduces ERBB2 protein levels, overcoming resistance to current therapies.
  • The developed technology presents a safe and effective method to control ERBB2 mRNA and other oncogenic signals.
Keywords:
3'UTR elementsERBB2 (HER2/neu)cancercancer treatmentdrug resistancemRNA overwritingmRNA stabilizing

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