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.
Highlights
Glioblastoma (GBM) is the most common and most lethal primary brain tumor, causing 12–14,000 deaths each year in the U.S alone [1]
The E2F1-regulated miR-17~92 cluster and its analogs are shown to be highly expressed in proneural GBM and in GBM stem cell-like (GSC) lines, suggesting the E2F cell cycle pathway might be a key driver in proneural GBM
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
Summary
Glioblastoma (GBM) is the most common and most lethal primary brain tumor, causing 12–14,000 deaths each year in the U.S alone [1]. MES subtype is aggressive and has greater vascularity, and it has been associated with NF1 lesions and with higher Akt, TGF-β, and NF-κB activity [3,4,5]. CL subtype is aggressive and is marked by frequent EGFR lesions [3,4,5]. The neural subtype has become controversial, as it is less distinct and may arise from substantial contamination of GBM samples with normal brain [5]. Major efforts have been underway to identify critical drivers of each GBM subtype, in hopes of gaining therapeutic leverage against them. Little progress has been made in uncovering key driver pathways and therapeutic vulnerabilities of the GBM subtypes, other than a few reports suggesting core circuitry of the MES subtype [6,7,8]
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