# CDK2 inhibition promotes neuronal differentiation in neuroblastoma

## TL;DR

This study shows that inhibiting CDK2 promotes neuronal differentiation in neuroblastoma, especially in MYCN-amplified tumors, suggesting a new therapeutic strategy.

## Contribution

The study identifies CDK2 as a MYCN target gene and shows that its inhibition enhances differentiation therapy in neuroblastoma.

## Key findings

- High CDK2 expression correlates with advanced, high-risk neuroblastoma and poor prognosis.
- CDK2 inhibition induces neuronal differentiation, particularly in MYCN-amplified tumors.
- Combining CDK2 inhibition with MYCN inhibition or retinoids enhances differentiation in vitro.

## Abstract

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.

The online version contains supplementary material available at 10.1038/s41598-026-38123-4.