ONC201 exerts oncogenic effects beyond its mitochondria-disturbing role in neuroblastoma subsets
- PMID: 40210723
- PMCID: PMC12078449
- DOI: 10.1007/s00109-025-02541-0
ONC201 exerts oncogenic effects beyond its mitochondria-disturbing role in neuroblastoma subsets
Abstract
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.
Keywords: ATRX; LGR5; Neuroblastoma; Non-MYCN-amplified cell line; ONC201.
© 2025. The Author(s).
Conflict of interest statement
Declarations. Ethics approval: The study adhered to the Declaration of Helsinki and received approval from the Institutional Review Board (IRB) of Chang Gung Medical Foundation (protocol code 201901723B0, dated 2 December 2019). The protocol for animal studies was also sanctioned by the Institutional Animal Care and Use Committee of Chang Gung Memorial Hospital (protocol code 2019091805, dated 1 January 2021, and 2023031303, dated 24 July 2023). Informed consent: The IRB of Chang Gung Medical Foundation approved the waiver of patient consent for protocol code 201901723B0, dated 2 December 2019, allowing the use of de-identified data. Conflict of interest: The authors declare no competing interests. Declaration of generative AI and AI-assisted technologies in the writing process: During the preparation of this work, the authors used chatGPT in order to improve language and readability. After using this tool/service, the authors reviewed and edited the content as needed and took full responsibility for the content of the publication.
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