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

doi:10.1038/s41388-018-0135-1

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 journal › Article › peer-review

64 Scopus citations

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 language	English (US)
Pages (from-to)	2850-2862
Number of pages	13
Journal	Oncogene
Volume	37
Issue number	21
DOIs	https://doi.org/10.1038/s41388-018-0135-1
State	Published - May 1 2018

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

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title = "Combined BET bromodomain and CDK2 inhibition in MYC-driven medulloblastoma",

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.",

author = "Sara Bolin and Anna Borgenvik and Persson, {Camilla U.} and Anders Sundstr{\"o}m and Jun Qi and Bradner, {James E.} and Weiss, {William A.} and Cho, {Yoon Jae} and Holger Weishaupt and Swartling, {Fredrik J.}",

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year = "2018",

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doi = "10.1038/s41388-018-0135-1",

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AU - Bolin, Sara

AU - Borgenvik, Anna

AU - Persson, Camilla U.

AU - Sundström, Anders

AU - Qi, Jun

AU - Bradner, James E.

AU - Weiss, William A.

AU - Cho, Yoon Jae

AU - Weishaupt, Holger

AU - Swartling, Fredrik J.

PY - 2018/5/1

Y1 - 2018/5/1

N2 - 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.

AB - 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.

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Combined BET bromodomain and CDK2 inhibition in MYC-driven medulloblastoma

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