The chemotherapeutic CX-5461 primarily targets TOP2B and exhibits selective activity in high-risk neuroblastoma.

Abstract

Survival in high-risk pediatric neuroblastoma has remained around 50% for the last 20 years, with immunotherapies and targeted therapies having had minimal impact. Here, we identify the small molecule CX-5461 as selectively cytotoxic to high-risk neuroblastoma and synergistic with low picomolar concentrations of topoisomerase I inhibitors in improving survival in vivo in orthotopic patient-derived xenograft neuroblastoma mouse models. CX-5461 recently progressed through phase I clinical trial as a first-in-human inhibitor of RNA-POL I. However, we also use a comprehensive panel of in vitro and in vivo assays to demonstrate that CX-5461 has been mischaracterized and that its primary target at pharmacologically relevant concentrations, is in fact topoisomerase II beta (TOP2B), not RNA-POL I. This is important because existing clinically approved chemotherapeutics have well-documented off-target interactions with TOP2B, which have previously been shown to cause both therapy-induced leukemia and cardiotoxicity-often-fatal adverse events, which can emerge several years after treatment. Thus, while we show that combination therapies involving CX-5461 have promising anti-tumor activity in vivo in neuroblastoma, our identification of TOP2B as the primary target of CX-5461 indicates unexpected safety concerns that should be examined in ongoing phase II clinical trials in adult patients before pursuing clinical studies in children.

• Authors: Min Pan, William C Wright, Richard H Chapple, Asif Zubair, Manbir Sandhu, Jake E Batchelder, Brandt C Huddle, Jonathan Low, Kaley B Blankenship, Yingzhe Wang, Brittney Gordon, Payton Archer, Samuel W Brady, Sivaraman Natarajan, Matthew J Posgai, John Schuetz, Darcie Miller, Ravi Kalathur, Siquan Chen, Jon Patrick Connelly, M Madan Babu, Michael A Dyer, Shondra M Pruett-Miller, Burgess B Freeman 3rd, Taosheng Chen, Lucy A Godley, Scott C Blanchard, Elizabeth Stewart, John Easton, Paul Geeleher
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 6468 (11 09 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 34753908 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2021. The Author(s).

Chemical References

• Benzothiazoles
• CX 5461
• Indoles
• Morpholines
• Naphthyridines
• Pyrimidines
• Sulfonamides
• ceralasertib
• DNA Topoisomerases, Type II

Topics

• Animals
• Benzothiazoles
• Blotting, Western
• Cell Line, Tumor
• DNA Topoisomerases, Type II (metabolism)
• Drug Synergism
• Enzyme Activation (drug effects)
• Flow Cytometry
• Fluorescent Antibody Technique
• Indoles (therapeutic use)
• Mice
• Mice, Nude
• Molecular Dynamics Simulation
• Morpholines (therapeutic use)
• Naphthyridines
• Neuroblastoma (drug therapy, metabolism)
• Pyrimidines (therapeutic use)
• Real-Time Polymerase Chain Reaction
• Sulfonamides (therapeutic use)