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Targeting replication stress in neuroblastoma by exploiting the synergistic potential of second generation RRM2 and CHK1 inhibitors

Tumor cells often cope with elevated levels of replication stress (RS) causing increased dependency on ATR-CHK1 signaling. We previously presented RRM2, the regulatory component of the ribonucleotide reductase (RNR) enzyme, as novel dependency in neuroblastoma (NB), in keeping with its role in RS re...

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Autori principali: Nelen, Iris H. (Autore) , Leys, Soetkin (Autore) , Bekaert, Sarah-Lee (Autore) , De Vloed, Fanny (Autore) , Martens, Fien (Autore) , Sanders, Ellen (Autore) , Praveena Enton Raj, Angeline (Autore) , Jeschke, Annika (Autore) , Ohmura, Shunya (Autore) , Grünewald, Thomas G. P. (Autore) , Mus, Liselot M. (Autore) , Lammens, Tim (Autore) , Van Roy, Nadine (Autore) , De Wilde, Bram (Autore) , Speleman, Frank (Autore) , Van Hemelryk, Annelies (Autore) , Depestel, Lisa (Autore) , Durinck, Kaat (Autore)
Natura: Article (Journal)
Lingua:inglese
Pubblicazione: 25 February 2026
In: Cell death & disease
Year: 2026, Volume: 17, Pages: 1-15
ISSN:2041-4889
DOI:10.1038/s41419-026-08514-6
Accesso online:Resolving-System, kostenfrei, Volltext: https://doi.org/10.1038/s41419-026-08514-6
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41419-026-08514-6
Testo
Note sull'autore:Iris H. Nelen, Soetkin Leys, Sarah-Lee Bekaert, Fanny De Vloed, Fien Martens, Ellen Sanders, Angeline Praveena Enton Raj, Annika Jeschke, Shunya Ohmura, Thomas G. P. Grünewald, Liselot M. Mus, Tim Lammens, Nadine Van Roy, Bram De Wilde, Frank Speleman, Annelies Van Hemelryk, Lisa Depestel and Kaat Durinck
Descrizione
Riassunto:Tumor cells often cope with elevated levels of replication stress (RS) causing increased dependency on ATR-CHK1 signaling. We previously presented RRM2, the regulatory component of the ribonucleotide reductase (RNR) enzyme, as novel dependency in neuroblastoma (NB), in keeping with its role in RS resistance. We identified strong synergism for combined RRM2-CHK1 inhibition using the iron chelator triapine and prexasertib respectively. To obtain direct RNR targeting, we evaluated a novel inhibitor, TAS1553, specifically disrupting the RNR complex in this study. Treatment with TAS1553 impedes cell growth and induces enhanced RS, DNA damage and apoptosis. We demonstrated strong synergism between TAS1553 and the CHK1 inhibitors prexasertib and SRA737 in both NB cell lines and tumoroids as well as in sarcoma cell lines. We confirm drug synergism in vivo in a NB zebrafish xenograft model, further underscoring the broad clinical potential of combinatorial RRM2-CHK1 inhibition. Altogether, this study paves the way for further preclinical testing of second generation RRM2 and CHK1 inhibitors such as TAS1553 and SRA737 in neuroblastoma and sarcomas.
Descrizione del documento:Gesehen am 21.08.2026
Descrizione fisica:Online Resource
ISSN:2041-4889
DOI:10.1038/s41419-026-08514-6

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