The MYCN 5' UTR as a therapeutic target in neuroblastoma

Marina P Volegova; Lauren E Brown; Ushashi Banerjee; Ruben Dries; Bandana Sharma; Alyssa Kennedy; John A Porco Jr; Rani E George

doi:10.1016/j.celrep.2024.114134

The MYCN 5' UTR as a therapeutic target in neuroblastoma

Cell Rep. 2024 Apr 23;43(5):114134. doi: 10.1016/j.celrep.2024.114134. Online ahead of print.

Authors

Marina P Volegova¹, Lauren E Brown², Ushashi Banerjee¹, Ruben Dries³, Bandana Sharma⁴, Alyssa Kennedy⁵, John A Porco Jr², Rani E George⁶

Affiliations

¹ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
² Boston University, Center for Molecular Discovery (BU-CMD), Boston, MA, USA; Boston University, Department of Chemistry, Boston, MA, USA.
³ Boston University School of Medicine, Computational Biomedicine, Boston, MA, USA.
⁴ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁵ Boston Children's Cancer and Blood Disorders Center, Pediatric Hematology/Oncology, Boston, MA, USA.
⁶ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA. Electronic address: rani_george@dfci.harvard.edu.

PMID: 38662542
DOI: 10.1016/j.celrep.2024.114134

Abstract

Tumor MYCN amplification is seen in high-risk neuroblastoma, yet direct targeting of this oncogenic transcription factor has been challenging. Here, we take advantage of the dependence of MYCN-amplified neuroblastoma cells on increased protein synthesis to inhibit the activity of eukaryotic translation initiation factor 4A1 (eIF4A1) using an amidino-rocaglate, CMLD012824. Consistent with the role of this RNA helicase in resolving structural barriers in 5' untranslated regions (UTRs), CMLD012824 increased eIF4A1 affinity for polypurine-rich 5' UTRs, including that of the MYCN and associated transcripts with critical roles in cell proliferation. CMLD012824-mediated clamping of eIF4A1 spanned the full lengths of mRNAs, while translational inhibition was mediated through 5' UTR binding in a cap-dependent and -independent manner. Finally, CMLD012824 led to growth inhibition in MYCN-amplified neuroblastoma models without generalized toxicity. Our studies highlight the key role of eIF4A1 in MYCN-amplified neuroblastoma and demonstrate the therapeutic potential of disrupting its function.

Keywords: CP: Cancer; CP: Molecular biology; MYCN; MYCN amplification; PAR-CLIP; amidino-rocaglate; eIF4A1; neuroblastoma; ribosome profiling; rocaglate; translation; translation regulation.