2. Academic Validation
  3. Palbociclib releases the latent differentiation capacity of neuroblastoma cells

Palbociclib releases the latent differentiation capacity of neuroblastoma cells

  • Dev Cell. 2023 Sep 9;S1534-5807(23)00443-4. doi: 10.1016/j.devcel.2023.08.028.
Kirsty M Ferguson 1,  Sarah L Gillen 1,  Lewis Chaytor 2,  Evon Poon 3,  Daniel Marcos 2,  Roshna Lawrence Gomez 4,  Laura M Woods 2,  Lidiya Mykhaylechko 2,  Louis Elfari 5,  Barbara Martins da Costa 3,  Yann Jamin 6,  Jason S Carroll 7,  Louis Chesler 3,  Fahad R Ali 4,  Anna Philpott 8
Affiliations

Affiliations

  • 1 Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, Cambridge CB2 0AW, UK.
  • 2 Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, Cambridge CB2 0AW, UK; Department of Oncology, University of Cambridge, Cambridge CB2 0XZ, UK.
  • 3 Division of Clinical Studies, The Institute of Cancer Research (ICR) and Royal Marsden NHS Trust, Sutton SM2 5NG, UK.
  • 4 College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Healthcare City, P.O. Box 505055, Dubai, United Arab Emirates.
  • 5 Wellcome-MRC Cambridge Stem Cell Institute Advanced Imaging Facility, Cambridge CB2 0AW, UK.
  • 6 Division of Radiotherapy and Imaging, The Institute of Cancer Research (ICR) and Royal Marsden NHS Trust, Sutton SM2 5NG, UK.
  • 7 Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK.
  • 8 Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, Cambridge CB2 0AW, UK; Department of Oncology, University of Cambridge, Cambridge CB2 0XZ, UK. Electronic address: ap113@cam.ac.uk.
PMID: 37734383 DOI: 10.1016/j.devcel.2023.08.028
Abstract

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.

Keywords

CDK4; CDK6; cell cycle; differentiation; neuroblastoma; palbociclib; retinoic acid.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-50767
    99.94%, CDK4/6 Inhibitor
    CDK