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
Affiliations
Marina P. Volegova
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA
Lauren E. Brown
Boston University, Center for Molecular Discovery (BU-CMD), Boston, MA, USA; Boston University, Department of Chemistry, Boston, MA, USA
Ushashi Banerjee
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA
Ruben Dries
Boston University School of Medicine, Computational Biomedicine, Boston, MA, USA
Bandana Sharma
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Alyssa Kennedy
Boston Children’s Cancer and Blood Disorders Center, Pediatric Hematology/Oncology, Boston, MA, USA
John A. Porco, Jr.
Boston University, Center for Molecular Discovery (BU-CMD), Boston, MA, USA; Boston University, Department of Chemistry, Boston, MA, USA
Rani E. George
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA; Corresponding author
Summary: 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.
