Transcriptional CDK inhibitors, CYC065 and THZ1 promote Bim-dependent apoptosis in primary and recurrent GBM through cell cycle arrest and Mcl-1 downregulation

Viktorija Juric, Lance Hudson, Joanna Fay, Cathy E. Richards, Hanne Jahns, Maïté Verreault, Franck Bielle, Ahmed Idbaih, Martine L.M. Lamfers, Ann M. Hopkins, Markus Rehm, Brona M. Murphy*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)

Abstract

Activation of cyclin-dependent kinases (CDKs) contributes to the uncontrolled proliferation of tumour cells. Genomic alterations that lead to the constitutive activation or overexpression of CDKs can support tumourigenesis including glioblastoma (GBM), the most common and aggressive primary brain tumour in adults. The incurability of GBM highlights the need to discover novel and more effective treatment options. Since CDKs 2, 7 and 9 were found to be overexpressed in GBM, we tested the therapeutic efficacy of two CDK inhibitors (CKIs) (CYC065 and THZ1) in a heterogeneous panel of GBM patient-derived cell lines (PDCLs) cultured as gliomaspheres, as preclinically relevant models. CYC065 and THZ1 treatments suppressed invasion and induced viability loss in the majority of gliomaspheres, irrespective of the mutational background of the GBM cases, but spared primary cortical neurons. Viability loss arose from G2/M cell cycle arrest following treatment and subsequent induction of apoptotic cell death. Treatment efficacies and treatment durations required to induce cell death were associated with proliferation velocities, and apoptosis induction correlated with complete abolishment of Mcl-1 expression, a cell cycle-regulated antiapoptotic Bcl-2 family member. GBM models generally appeared highly dependent on Mcl-1 expression for cell survival, as demonstrated by pharmacological Mcl-1 inhibition or depletion of Mcl-1 expression. Further analyses identified CKI-induced Mcl-1 loss as a prerequisite to establish conditions at which the BH3-only protein Bim can efficiently induce apoptosis, with cellular Bim amounts strongly correlating with treatment efficacy. CKIs reduced proliferation and promoted apoptosis also in chick embryo xenograft models of primary and recurrent GBM. Collectively, these studies highlight the potential of these novel CKIs to suppress growth and induce cell death of patient-derived GBM cultures in vitro and in vivo, warranting further clinical investigation.

Original languageEnglish
Article number763
JournalCell Death and Disease
Volume12
Issue number8
DOIs
Publication statusPublished - 3 Aug 2021

Bibliographical note

Funding Information:
We wish to thank the patients who kindly donated their samples and made this study possible. MV, AI, MLML, MR and BMM receive support from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement #766069 (GLIO-TRAIN). VJ kindly acknowledges support for her work by the Irish Association for Cancer Research (IACR Educational Grant). MR acknowledges support by the Deutsche Forschungsgemeinschaft (MO3226 4/1). AMH acknowledges support from Science Foundation Ireland (13/IA/1994) and the Health Research Board (HRA-POR-2014-545).

Publisher Copyright:
© 2021, The Author(s).

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