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<p>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 <i>MYCN</i>-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, <i>MYCN</i>-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 <i>MYCN</i>-amplified subtype. Further, we establish CDK2 as a MYCN target gene that modulate the MYC-pathway in <i>MYCN</i>-amplified NB. Notably, pharmacological inhibition of CDK2 in combination with MYCN inhibition or all-<i>trans</i>-retinoic acid (ATRA) differentiation therapy enhances neuronal differentiation in vitro. These results reveal an important function of CDK2 in NB and highlight CDK2&#xa0;inhibition alone or in combination with MYC inhibitors and retinoids as a potential strategy for differentiation therapy in NB.</p>

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CDK2 inhibition promotes neuronal differentiation in neuroblastoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月6日

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  • Mohammad Alzrigat,
  • Loay Mahmoud,
  • Ada Nursel Topçu,
  • Marta Valenti,
  • Lu Zhang,
  • Puck Veen,
  • Fabian John,
  • Wesam Bazzar,
  • Kaisa Lehti,
  • Lars-Gunnar Larsson

摘要

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.