Combined BET bromodomain and CDK2 inhibition in MYC-driven medulloblastoma

Sara Bolin, Anna Borgenvik, Camilla U. Persson, Anders Sundström, Jun Qi, James E. Bradner, William A. Weiss, Yoon-Jae Cho, Holger Weishaupt, Fredrik J. Swartling

Research output: Contribution to journalArticle

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Abstract

Medulloblastoma (MB) is the most common malignant brain tumor in children. MYC genes are frequently amplified and correlate with poor prognosis in MB. BET bromodomains recognize acetylated lysine residues and often promote and maintain MYC transcription. Certain cyclin-dependent kinases (CDKs) are further known to support MYC stabilization in tumor cells. In this report, MB cells were suppressed by combined targeting of MYC expression and MYC stabilization using BET bromodomain inhibition and CDK2 inhibition, respectively. Such combination treatment worked synergistically and caused cell cycle arrest as well as massive apoptosis. Immediate transcriptional changes from this combined MYC blockade were found using RNA-Seq profiling and showed remarkable similarities to changes in MYC target gene expression when MYCN was turned off with doxycycline in our MYCN-inducible animal model for Group 3 MB. In addition, the combination treatment significantly prolonged survival as compared to single-agent therapy in orthotopically transplanted human Group 3 MB with MYC amplifications. Our data suggest that dual inhibition of CDK2 and BET bromodomains can be a novel treatment approach for suppressing MYC-driven cancer.

Original languageEnglish (US)
Pages (from-to)2850-2862
Number of pages13
JournalOncogene
Volume37
Issue number21
DOIs
StatePublished - May 1 2018

Fingerprint

Medulloblastoma
Cyclin-Dependent Kinases
Doxycycline
Therapeutics
Cell Cycle Checkpoints
Brain Neoplasms
Lysine
Neoplasms
Animal Models
RNA
Apoptosis
Gene Expression
Survival
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Bolin, S., Borgenvik, A., Persson, C. U., Sundström, A., Qi, J., Bradner, J. E., ... Swartling, F. J. (2018). Combined BET bromodomain and CDK2 inhibition in MYC-driven medulloblastoma. Oncogene, 37(21), 2850-2862. https://doi.org/10.1038/s41388-018-0135-1

Combined BET bromodomain and CDK2 inhibition in MYC-driven medulloblastoma. / Bolin, Sara; Borgenvik, Anna; Persson, Camilla U.; Sundström, Anders; Qi, Jun; Bradner, James E.; Weiss, William A.; Cho, Yoon-Jae; Weishaupt, Holger; Swartling, Fredrik J.

In: Oncogene, Vol. 37, No. 21, 01.05.2018, p. 2850-2862.

Research output: Contribution to journalArticle

Bolin, S, Borgenvik, A, Persson, CU, Sundström, A, Qi, J, Bradner, JE, Weiss, WA, Cho, Y-J, Weishaupt, H & Swartling, FJ 2018, 'Combined BET bromodomain and CDK2 inhibition in MYC-driven medulloblastoma', Oncogene, vol. 37, no. 21, pp. 2850-2862. https://doi.org/10.1038/s41388-018-0135-1
Bolin S, Borgenvik A, Persson CU, Sundström A, Qi J, Bradner JE et al. Combined BET bromodomain and CDK2 inhibition in MYC-driven medulloblastoma. Oncogene. 2018 May 1;37(21):2850-2862. https://doi.org/10.1038/s41388-018-0135-1
Bolin, Sara ; Borgenvik, Anna ; Persson, Camilla U. ; Sundström, Anders ; Qi, Jun ; Bradner, James E. ; Weiss, William A. ; Cho, Yoon-Jae ; Weishaupt, Holger ; Swartling, Fredrik J. / Combined BET bromodomain and CDK2 inhibition in MYC-driven medulloblastoma. In: Oncogene. 2018 ; Vol. 37, No. 21. pp. 2850-2862.
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