帕博西利布
神经母细胞瘤
生物
维甲酸
癌症研究
细胞分化
细胞生物学
细胞生长
癌症
基因
遗传学
细胞培养
转移性乳腺癌
乳腺癌
作者
Kirsty M. Ferguson,Sarah L. Gillen,Lewis Chaytor,Evon Poon,Daniel Marcos,Roshna Lawrence Gomez,Laura Woods,Lidiya Mykhaylechko,Louis M. Elfari,Barbara Martins Da Costa,Yann Jamin,Jason S. Carroll,Louis Chesler,Fahad Ali,Anna Philpott
标识
DOI:10.1016/j.devcel.2023.08.028
摘要
Neuroblastoma is the most common extracranial solid tumor in infants, arising from developmentally stalled neural crest-derived cells. Driving tumor differentiation is a promising therapeutic approach for this devastating disease. Here, we show that the CDK4/6 inhibitor palbociclib not only inhibits proliferation but induces extensive neuronal differentiation of adrenergic neuroblastoma cells. Palbociclib-mediated differentiation is manifested by extensive phenotypic and transcriptional changes accompanied by the establishment of an epigenetic program driving expression of mature neuronal features. In vivo palbociclib significantly inhibits tumor growth in mouse neuroblastoma models. Furthermore, dual treatment with retinoic acid resets the oncogenic adrenergic core regulatory circuit of neuroblastoma cells, further suppresses proliferation, and can enhance differentiation, altering gene expression in ways that significantly correlate with improved patient survival. We therefore identify palbociclib as a therapeutic approach to dramatically enhance neuroblastoma differentiation efficacy that could be used in combination with retinoic acid to improve patient outcomes.
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