The chemotherapeutic CX-5461 primarily targets TOP2B and exhibits selective activity in high-risk neuroblastoma
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,
Taosheng Chen,
Lucy A. Godley,
Scott C. Blanchard,
Elizabeth Stewart,
John Easton () and
Paul Geeleher ()
Additional contact information
Min Pan: St. Jude Children’s Research Hospital
William C. Wright: St. Jude Children’s Research Hospital
Richard H. Chapple: St. Jude Children’s Research Hospital
Asif Zubair: St. Jude Children’s Research Hospital
Manbir Sandhu: St. Jude Children’s Research Hospital
Jake E. Batchelder: St. Jude Children’s Research Hospital
Brandt C. Huddle: Weill Cornell Medicine
Jonathan Low: St. Jude Children’s Research Hospital
Kaley B. Blankenship: St. Jude Children’s Research Hospital
Yingzhe Wang: Preclinical Pharmacokinetic Shared Resource, St. Jude Children’s Research Hospital
Brittney Gordon: St. Jude Children’s Research Hospital
Payton Archer: St. Jude Children’s Research Hospital
Samuel W. Brady: St. Jude Children’s Research Hospital
Sivaraman Natarajan: St. Jude Children’s Research Hospital
Matthew J. Posgai: The University of Chicago
John Schuetz: St. Jude Children’s Research Hospital
Darcie Miller: St. Jude Children’s Research Hospital
Ravi Kalathur: St. Jude Children’s Research Hospital
Siquan Chen: Cellular Screening Center, The University of Chicago
Jon Patrick Connelly: St. Jude Children’s Research Hospital
M. Madan Babu: St. Jude Children’s Research Hospital
Michael A. Dyer: St. Jude Children’s Research Hospital
Shondra M. Pruett-Miller: St. Jude Children’s Research Hospital
Burgess B. Freeman: Preclinical Pharmacokinetic Shared Resource, St. Jude Children’s Research Hospital
Taosheng Chen: St. Jude Children’s Research Hospital
Lucy A. Godley: The University of Chicago
Scott C. Blanchard: St. Jude Children’s Research Hospital
Elizabeth Stewart: St. Jude Children’s Research Hospital
John Easton: St. Jude Children’s Research Hospital
Paul Geeleher: St. Jude Children’s Research Hospital
Nature Communications, 2021, vol. 12, issue 1, 1-20
Abstract:
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.
Date: 2021
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (3)
Downloads: (external link)
https://www.nature.com/articles/s41467-021-26640-x Abstract (text/html)
Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.
Export reference: BibTeX
RIS (EndNote, ProCite, RefMan)
HTML/Text
Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26640-x
Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/
DOI: 10.1038/s41467-021-26640-x
Access Statistics for this article
Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie
More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().