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Nat Commun ; 12(1): 6468, 2021 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-34753908

RESUMO

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.


Assuntos
DNA Topoisomerases Tipo II/metabolismo , Indóis/uso terapêutico , Morfolinas/uso terapêutico , Neuroblastoma/tratamento farmacológico , Neuroblastoma/metabolismo , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Animais , Benzotiazóis , Western Blotting , Linhagem Celular Tumoral , Sinergismo Farmacológico , Ativação Enzimática/efeitos dos fármacos , Citometria de Fluxo , Imunofluorescência , Camundongos , Camundongos Nus , Simulação de Dinâmica Molecular , Naftiridinas , Reação em Cadeia da Polimerase em Tempo Real
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