神经母细胞瘤是婴儿中最常见的颅外实性肿瘤，起源于发育停滞的神经嵴来源细胞。驱动肿瘤分化是治疗这种毁灭性疾病的一种有前途的方法。在这里，我们展示出CDK4/6抑制剂帕博西利能够不仅抑制增殖，还能诱导肾上腺能神经母细胞瘤细胞的广泛神经分化。帕博西利诱导的分化表现为广泛的表型和转录变化，伴随着建立起促进成熟神经特征表达的表观遗传程序。在体内，帕博西利显著抑制小鼠神经母细胞瘤模型的肿瘤生长。此外，与视黄酸的双重治疗可重置神经母细胞瘤细胞的致癌肾上腺能核心调控回路，进一步抑制增殖，并且能够增强分化，通过改变基因表达方式，与患者生存水平显著相关。因此，我们确定帕博西利为一种能够显著增强神经母细胞瘤分化效力的治疗方法，可与视黄酸联合应用以改善患者预后。版权所有 © 2023 作者。由Elsevier Inc发布。保留所有权利。

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.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.