The MYCN 5' UTR as a therapeutic target in neuroblastoma
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Published version
Date
2024-04-23
Authors
Volegova, Marina P.
Brown, Lauren E.
Banerjee, Ushashi
Dries, Ruben
Sharma, Bandana
Kennedy, Alyssa
Porco, John A.
George, Rani E.
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Published version
OA Version
Citation
M.P. Volegova, L.E. Brown, U. Banerjee, R. Dries, B. Sharma, A. Kennedy, J.A. Porco, R.E. George. 2024. "The MYCN 5' UTR as a therapeutic target in neuroblastoma." Cell Reports, Volume 43, Issue 5, pp.114134-. https://doi.org/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.
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