{Reference Type}: Journal Article
{Title}: The MYCN 5' UTR as a therapeutic target in neuroblastoma.
{Author}: Volegova MP;Brown LE;Banerjee U;Dries R;Sharma B;Kennedy A;Porco JA;George RE;
{Journal}: Cell Rep
{Volume}: 43
{Issue}: 5
{Year}: 2024 May 28
暂无{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.