Oncotarget

Research Papers:

CDK4/6 inhibition is more active against the glioblastoma proneural subtype

Ming Li, Aizhen Xiao, Desiree Floyd, Inan Olmez, Jeongwu Lee, Jakub Godlewski, Agnieszka Bronisz, Krishna P.L. Bhat, Erik P. Sulman, Ichiro Nakano and Benjamin Purow _

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Oncotarget. 2017; 8:55319-55331. https://doi.org/10.18632/oncotarget.19429

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Abstract

Ming Li1,2, Aizhen Xiao1, Desiree Floyd1, Inan Olmez1, Jeongwu Lee3, Jakub Godlewski4, Agnieszka Bronisz4, Krishna P.L. Bhat5, Erik P. Sulman6, Ichiro Nakano7 and Benjamin Purow1

1Neuro-Oncology Division, Department of Neurology, University of Virginia, Charlottesville, VA, USA

2The Experiment Center, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China

3Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

4Department of Neurosurgery, Brigham and Women’s Hospital, Boston, MA, USA

5Departments of Pathology, MD Anderson Cancer Center, Houston, TX, USA

6Radiation Oncology, MD Anderson Cancer Center, Houston, TX, USA

7Department of Neurosurgery, University of Alabama, Birmingham, AL, USA

Correspondence to:

Benjamin Purow, email: [email protected]

Keywords: glioblastoma, palbociclib, proneural, mesenchymal, CDK4/6

Received: March 10, 2017     Accepted: July 12, 2017     Published: July 21, 2017

ABSTRACT

Glioblastoma (GBM) is the most common and lethal brain tumor. Gene expression profiling has classified GBM into distinct subtypes, including proneural, mesenchymal, and classical, and identifying therapeutic vulnerabilities of these subtypes is an extremely high priority. We leveraged The Cancer Genome Atlas (TCGA) data, in particular for microRNA expression, to seek druggable core pathways in GBM. The E2F1-regulated miR-17~92 cluster and its analogs are shown to be highly expressed in proneural GBM and in GSC lines, suggesting the E2F cell cycle pathway might be a key driver in proneural GBM. Consistently, CDK4/6 inhibition with palbociclib preferentially inhibited cell proliferation in vitro in a majority of proneural GSCs versus those of other subtypes. Palbociclib treatment significantly prolonged survival of mice with established intracranial xenografts of a proneural GSC line. We show that most of these sensitive PN GSCs expressed higher levels of CDK6 and had intact Rb1, while two GSC lines with CDK4 overexpression and null Rb1 were highly resistant to palbociclib. Importantly, palbociclib treatment of proneural GSCs upregulated mesenchymal-associated markers and downregulated proneural-associated markers, suggesting that CDK4/6 inhibition induced proneural-mesenchymal transition and underscoring the enhanced role of the E2F cell cycle pathway in the proneural subtype. Lastly, the combination of palbociclib and N,N-diethylaminobenzaldehyde, an inhibitor of the mesenchymal driver ALDH1A3, showed strong synergistic inhibitory effects against proneural GSC proliferation. Taken together, our results reveal that proneural GBM has increased vulnerability to CDK4/6 inhibition, and the proneural subtype undergoes dynamic reprogramming upon palbociclib treatment—suggesting the need for a combination therapeutic strategy.


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