A drug that induces the microRNA miR-124 enables differentiation of retinoic acid–resistant neuroblastoma cells
Menée in vitro, cette étude met en évidence l'intérêt d'un inhibiteur de tyrosine et de phosphoinositide kinase (PP121) pour induire la synthèse du suppresseur de tumeur miR-124 et favoriser ainsi la différenciation des cellules de neuroblastome résistantes à l'acide rétinoïque
Tumor cell heterogeneity in neuroblastoma, a pediatric cancer arising from neural crest–derived progenitor cells, presents clinical challenges. Unlike adrenergic (ADRN) neuroblastoma cells, neuroblastoma cells with a mesenchymal (MES) identity are resistant to chemotherapy and retinoid therapy, which contributes to relapses and treatment failures. We explored whether up-regulation of the neurogenic, tumor suppressor microRNA miR-124 could promote the differentiation of retinoic acid–resistant MES neuroblastoma cells. Leveraging our screen for miRNA-modulatory small molecules, we identified and validated the tyrosine and phosphoinositide kinase inhibitor PP121 as a robust inducer of miR-124. Combining PP121 and BDNF-activating bufalin synergistically arrested proliferation and promoted the sustained differentiation of MES/heterogeneous SK-N-AS cells over several weeks. This protocol also resulted in the differentiation of multiple MES neuroblastoma and glioblastoma cell lines. RNA-seq analysis of differentiated MES/heterogeneous SK-N-AS cells revealed the replacement of the ADRN core regulatory circuitry with circuitries associated with chromaffin cells and Schwann cell precursors. Furthermore, differentiation was associated with inhibition of the CDK4/CDK6 pathway and activation of a transcriptional program that correlated with improved outcomes for patients with neuroblastoma. Our findings suggest an approach with translational potential to induce the differentiation of therapy-resistant cancers of the nervous system. Moreover, these long-lived, differentiated cells could be used to study mechanisms underlying cancer biology and therapies. An alternative strategy to differentiate neuroblastoma is to induce miR-124 with the kinase inhibitor PP121. Neuroblastoma is a pediatric cancer that originates from progenitor cells arising from the neural crest. A subtype of this cancer is characterized by the presence of immature mesenchymal (MES) cells, which are resistant to standard treatments, including retinoic acid therapy. Nguyen et al. screened small-molecule activators of the microRNA miR-124, which drives differentiation in neuroblastoma cells, and identified PP121, a drug that inhibits tyrosine and phosphoinositide kinases. In combination with the BDNF-activating drug bufalin, PP121 inhibited the proliferation and enabled the differentiation of retinoic acid–resistant MES neuroblastoma cell lines. This work provides an additional strategy for differentiating treatment-resistant MES cells associated with high-risk neuroblastomas. —Amy E. Baek
Science Signaling , article en libre accès 2025