CDK2 inhibition promotes neuronal differentiation in neuroblastoma.

Neuroblastoma (NB) is a childhood tumor arising from neural crest-derived progenitor cells. Cyclin dependent kinase 2 (CDK2) has been suggested to be a promising therapeutic target in NB especially MYCN-amplified tumors. How CDK2 contributes to the development of NB is not fully understood. Here, we demonstrate that high CDK2 expression in NB correlates with advanced and high-risk disease, MYCN-amplification, poor prognosis, and undifferentiated tumors. We uncovered that CDK2 genetic or pharmacological inhibition induces neuronal differentiation in human NB cell lines, which effect is in general more prominent in the MYCN-amplified subtype. Further, we establish CDK2 as a MYCN target gene that modulate the MYC-pathway in MYCN-amplified NB. Notably, pharmacological inhibition of CDK2 in combination with MYCN inhibition or all-trans-retinoic acid (ATRA) differentiation therapy enhances neuronal differentiation in vitro. These results reveal an important function of CDK2 in NB and highlight CDK2 inhibition alone or in combination with MYC inhibitors and retinoids as a potential strategy for differentiation therapy in NB. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-38123-4.