The MYCN 5′ UTR as a therapeutic target in neuroblastoma

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. [Display omitted] •MYCN-amplified neuroblastomas have preferentially increased expression of eIF4A1•Amidino-rocaglates augment eIF4A1 binding across the full length of cellular mRNAs•MYCN mRNA is directly inhibited by amidino-rocaglates•Polypurine ranking of mRNA 5′ UTRs predicts amidino-rocaglate sensitivity in neuroblastoma MYCN amplification is a key driver of high-risk neuroblastoma. Volegova et al. capitalize on the dependence of MYCN-amplified neuroblastoma cells on increased protein synthesis by using amidino-rocaglates to inhibit translation initiation factor eIF4A1, resulting in direct targeting of the MYCN mRNA and selective cytotoxicity in animal models.