SUMOylation is a Therapeutic Vulnerability in High-risk Neuroblastoma

Neuroblastoma (NB) is one of the most common solid malignancies in children, and high-risk patients have poor prognosis, underscoring the need for novel therapeutic agents. The small ubiquitin-like modifier (SUMO) is a reversible post-translational modification that regulates various protein functions, and the first-in-class SUMOylation inhibitor TAK-981 (subasumstat) is currently in clinical trials in adult cancer patients. However, the role of SUMOylation in NB pathogenesis remains poorly characterized. We show that SUMOylation- catalyzing enzymes, SAE1 , SAE2 , and UBE2I , are highly expressed in malignant neuroendocrine cells, and their expression correlate with poor survival in NB patients and associate with advanced stage, MYCN amplifications, and downregulation of late differentiation markers. The peripheral nervous system lineage and NB cell lines are highly sensitive to the CRISPR knockout of SAE1 and SAE2 , suggesting SUMOylation as promising therapeutic target in NB. Accordingly, TAK-981-mediated inhibition of SUMOylation reduces growth of NB cells in both in vitro and in vivo models through induction of apoptosis and perturbation of differentiation-associated pathways. Sensitivity to SUMOylation inhibition is greatest in NB cells with low expression of favorable late neuroblast markers and is independent of MYCN amplification status. Moreover, TAK-981 is effective in combination with differentiation-inducing all-trans retinoic acid and the DNA methyltransferase inhibitor decitabine. Mechanistically, combination of TAK-981 and retinoic acid potently downregulates retinoic acid receptor alpha (RARα) expression, whereas inhibition of SUMOylation combined with decitabine induces a strong accumulation of DNA damage. Taken together, these findings establish SUMO pathway components as potential prognostic markers and SUMOylation as a therapeutic vulnerability in high-risk NB.