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

• DOI: 10.1038/s41467-021-26640-x
• Publication Date: 2021-11-09T11:02:38Z
• 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...; Burgess B. Freeman; Taosheng Chen; Lucy A. Godley; Scott C. Blanchard; Elizabeth Stewart; John Easton; Paul Geeleher
• Keywords: Cardiotoxicity

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