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The MYCN 5' UTR as a therapeutic target in neuroblastoma

Marina P Volegova1, Lauren E Brown2, Ushashi Banerjee1

  • 1Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA.

Cell Reports
|April 25, 2024
PubMed

Insights

Targeting MYCN-amplified neuroblastoma, researchers inhibited eukaryotic translation initiation factor 4A1 (eIF4A1) with CMLD012824. This drug reduced tumor growth without toxicity, showing therapeutic potential.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • MYCN amplification defines high-risk neuroblastoma, posing therapeutic challenges.
  • Neuroblastoma cells with MYCN amplification exhibit heightened dependence on protein synthesis.

Purpose of the Study:

  • To investigate the therapeutic potential of inhibiting eukaryotic translation initiation factor 4A1 (eIF4A1) in MYCN-amplified neuroblastoma.
  • To explore the mechanism of action of the eIF4A1 inhibitor CMLD012824.

Main Methods:

  • Utilized an amidino-rocaglate, CMLD012824, to inhibit eIF4A1 activity.
  • Assessed the impact of CMLD012824 on mRNA translation, focusing on 5' untranslated regions (UTRs).
  • Evaluated the efficacy and toxicity of CMLD012824 in MYCN-amplified neuroblastoma models.

Main Results:

  • CMLD012824 enhanced eIF4A1 binding to polypurine-rich 5' UTRs of MYCN and proliferation-associated transcripts.
  • Inhibition of translation occurred in a cap-dependent and -independent manner via 5' UTR binding.
  • CMLD012824 demonstrated significant growth inhibition in neuroblastoma models with MYCN amplification, showing no generalized toxicity.

Conclusions:

  • eIF4A1 plays a critical role in MYCN-amplified neuroblastoma.
  • Disrupting eIF4A1 function with CMLD012824 presents a promising therapeutic strategy for high-risk neuroblastoma.
Keywords:
CP: CancerCP: Molecular biologyMYCNMYCN amplificationPAR-CLIPamidino-rocaglateeIF4A1neuroblastomaribosome profilingrocaglatetranslationtranslation regulation

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