ONC201 exerts oncogenic effects beyond its mitochondria-disturbing role in neuroblastoma subsets.

Neuroblastoma (NB) is a formidable challenge in pediatric oncology due to its intricate molecular landscape, necessitating multifaceted therapeutic approaches. ONC201 is an imipridone antibiotic compound with a promising drug candidate leveraging its potent anticancer properties against the mitochondrial proteases ClpP and ClpX. Despite demonstrating early clinical promise, particularly in MYCN-amplified NB, its efficacy in non-MYCN-amplified NB remains a subject worthy of investigation. In this study, we extended the coverage of ONC201 to treat non-MYCN-amplified NB, and our data implicated ONC201's inability to reduce tumor growth in animal models harboring SK-N-AS or SK-N-FI cell lines. Interestingly, ONC201 induced the expression of oncogenic markers c-Myc and LGR5 while downregulating the tumor suppressor ATRX. While it fails to attenuate tumor neovascularization in non-MYCN-amplified NB xenografts, its effectiveness differs from that of its MYCN-amplified counterpart. Rho zero (ρ0)-SK-N-AS cells treated with ONC201 showed comparable observed trends in parental SK-N-AS cells, including LGR5 upregulation and ATRX downregulation, suggesting that ONC201's multifaceted actions extend beyond mitochondrial targets. Our elucidation highlights the need to discern molecular signatures when deploying ONC201 monotherapy against NB, which lacks MYCN-amplification.