Cyclin-dependent kinase 7 is a therapeutic target in high-grade glioma

Oncogenesis
S A GreenallT G Johns

Abstract

High-grade glioma (HGG) is an incurable brain cancer. The transcriptomes of cells within HGG tumors are highly heterogeneous. This renders the tumors unresponsive or able to adapt to therapeutics targeted at single pathways, thereby causing treatment failure. To overcome this, we focused on cyclin-dependent kinase 7 (CDK7), a ubiquitously expressed molecule involved in two major drivers of HGG pathogenesis: cell cycle progression and RNA polymerase-II-based transcription. We tested the activity of THZ1, an irreversible CDK7 inhibitor, on patient-derived primary HGG cell lines and ex vivo HGG patient tissue slices, using proliferation assays, microarray analysis, high-resolution respirometry, cell cycle analysis and in vivo tumor orthografts. The cellular processes affected by CDK7 inhibition were analyzed by reverse transcriptase-quantitative PCR, western blot, flow cytometry and immunofluorescence. THZ1 perturbed the transcriptome and disabled CDK activation, leading to cell cycle arrest at G2 and DNA damage. THZ1 halted transcription of the nuclear-encoded mitochondrial ribosomal genes, reducing mitochondrial translation and oxidative respiration. It also inhibited the expression of receptor tyrosine kinases such as epidermal...Continue Reading

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Citations

Apr 10, 2018·Chemical Communications : Chem Comm·Clement Opoku-TemengHerman O Sintim
May 31, 2018·Future Medicinal Chemistry·Amy B HeptinstallIan R Hardcastle
Aug 27, 2018·Journal of Cellular Biochemistry·Liqiang ZhongKaijian Lei
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Mar 10, 2020·Journal of Medicinal Chemistry·Sarah DiabShudong Wang
Sep 12, 2021·Nature Reviews. Molecular Cell Biology·Helen K MatthewsRobertus A M de Bruin

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Datasets Mentioned

BETA
GSE94931

Methods Mentioned

BETA
PCR
flow cytometry
nuclear translocation
electrophoresis

Software Mentioned

Bioconductor
FlowJo
limma
Odyssey
Excel
GraphPad
OROBOROS Oxygraph
ImageJ
Prism

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